RARE DISEASE
Progressive supranuclear palsy
Progressive supranuclear palsy
Progressive supranuclear palsy
Synonyms: PSP syndrome
Synonyms: PSP syndrome
Synonyms: PSP syndrome
Drug discovery
32
drugs
With orphan designations
Overview
Progressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy affecting brainstem and basal ganglia, characterized by postural instability, vertical gaze palsy, pseudobulbar symptoms, and frontal cognitive dysfunction. Diagnosis is often delayed due to overlap with Parkinson’s disease and dementia [1][5][12]. Neuropathology involves 4-repeat tau aggregation, with no disease-modifying therapies available [8][16]. Median survival is 4.9 years, with complications including falls, dysphagia, and aspiration pneumonia [2][11].
Therapies
Symptomatic: Levodopa (limited efficacy), amantadine, antidepressants (SSRIs/tricyclics), and atypical antipsychotics for mood/behavioral symptoms [3][6][18].
Non-pharmacologic: Physical/occupational therapy, prism glasses, weighted walkers, gastrostomy for dysphagia [1][6][13].
Research: Anti-tau therapies (e.g., monoclonal antibodies), neuroprotective agents, and DBS in clinical trials [8][16].
Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
712 drug discovery papers about Progressive supranuclear palsy, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
712 drug discovery papers about Progressive supranuclear palsy, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-03 | Elevated DYRK1A in Primary Tauopathies and Therapeutic Targeting with the Brain-Penetrant Inhibitor DYR533.
Neurodegenerative disorders are increasing in prevalence, yet disease-modifying therapies remain limited. Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) phosphorylates tau and regulates inflammatory signaling, making it a potential therapeutic target for neurodegenerative diseases. To investigate the relevance of DYRK1A to primary tauopathies, we first evaluated DYRK1A protein levels in the superior frontal gyrus of individuals with Pick's disease, corticobasal degeneration, and progressive supranuclear palsy. DYRK1A protein expression was significantly elevated in individuals with primary tauopathies compared with healthy controls and positively correlated with Braak stage. Conversely, DYRK1A levels inversely correlated with last Mini-Mental State Examination (MMSE) scores and brain weight, linking elevated DYRK1A expression to disease severity. We next developed DYR533, a selective, orally bioavailable, brain-penetrant small-molecule DYRK1A inhibitor with an S(35) score of 1.4 nM based on a 403-target KINOMEscan assay. Mechanistically, DYR533 prevented the autophosphorylation of newly translated DYRK1A, rendering the kinase inactive and thereby inhibiting phosphorylation of downstream substrates. We next evaluated the therapeutic efficacy of DYR533 in the PS19 mouse model of primary tauopathy, assessing tau hyperphosphorylation, neuroinflammation, motor function, and spatial cognition. DYR533 reduced tau hyperphosphorylation at threonine 217, threonine 181, and serine 396, and attenuated the expression of neuroinflammatory cytokines and chemokines implicated in disease progression. In PS19 mice, DYR533 treatment produced modest improvements on behavior. Together, these findings establish an association between elevated DYRK1A and disease severity in human primary tauopathies and demonstrate that pharmacological inhibition of DYRK1A with DYR533 reduces pathological tau phosphorylation and neuroinflammatory signaling in vivo.
2026-08-21 | Phase 2a Randomized Controlled Trial of TPN-101, A Nucleoside Reverse Transcriptase Inhibitor, in Progressive Supranuclear Palsy.
Preclinical and human brain postmortem studies indicate that progressive supranuclear palsy (PSP) is associated with increased expression of the retrotransposon Long Interspersed Nuclear Element-1 (L1Hs). L1Hs activity initiates an innate immune response that leads to neuroinflammation and neurodegeneration, which can be attenuated by inhibiting the L1Hs-encoded reverse transcriptase. TPN-101 is a potent inhibitor of the L1Hs reverse transcriptase. The objective of this study was to assess the safety, pharmacokinetics, and biomarker and clinical effects of TPN-101 in patients with PSP. A double-blind, placebo-controlled, parallel-group study randomly assigned patients with probable PSP to receive TPN-101 100, 200, or 400 mg, or placebo daily for 24 weeks. Following the double-blind period, all patients received open-label TPN-101 400 mg daily for 24 weeks. The primary outcome was the incidence and severity of treatment-emergent adverse events. Biomarker, clinical, and TPN-101 pharmacokinetic assessments were conducted throughout the study. Forty-two patients were randomly assigned to TPN-101 100 mg (N = 11), 200 mg (N = 10), 400 mg (N = 11), or placebo (N = 10). TPN-101 was well tolerated, with no notable safety differences between any drug dose and placebo. Greater reductions in cerebrospinal fluid levels of neurofilament light chain with increasing dose were seen in patients taking TPN-101 during the double-blind period, compared with an increase in the placebo arm. There were no differences among the treatments on the Progressive Supranuclear Palsy Rating Scale during the double-blind period. The safety, pharmacokinetics, and reductions in biomarkers of neuroinflammation and neurodegeneration warrant future trials powered to detect clinical effects of TPN-101 in PSP. © 2026 International Parkinson and Movement Disorder Society.
2026-08-19 | Astrocytic 4R-tau pathology drives aquaporin-4 (AQP4) mislocalization, glymphatic dysfunction, and neurotransmitter dysregulation in mice.
Progressive supranuclear palsy (PSP) is a severe neurodegenerative tauopathy defined by astrocytic tau inclusions and parkinsonism. The link between astrogliopathy and compromised cerebral fluid dynamics remains unclear. We generated a glial fibrillary acidic protein (GFAP)-e (2A-mMAPT(4R) cDNA) transgenic mouse model (GFAP/tau Tg) with astrocyte-specific expression of 4-repeat (4R) tau to investigate mechanisms underlying astrocytic tau pathology as seen in PSP. Both male and female mice were used in this study. GFAP/tau Tg mice exhibited robust astrocytic hyperphosphorylated tau (p-tau) deposition and activation. Mechanistically, this pathology caused dysregulation of the dystrophin-associated complex (DAC), leading to a critical loss of Aquaporin 4 (AQP4) polarity and aberrant AQP4 distribution in perivascular endfeet. This DAC-AQP4 axis disruption critically impaired cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, subsequently causing deficient glymphatic fluid drainage and excessive ISF accumulation. This fluid stasis was correlated with a significant decline in the synaptic neurotransmitters dopamine (DA) and acetylcholine (ACh). Ultimately, these pathological events manifested as parkinsonian-like motor dysfunction and cognitive deficits in the transgenic mice. Our study clarifies a novel, sequential mechanism linking astrocytic 4R tauopathy to glymphatic circulation failure and neurochemical deficits that recapitulates key astroglial pathological features of PSP. These findings establish the glymphatic system as a compelling therapeutic target for treating neurodegenerative disorders linked to astrogliopathy.Significance Statement Astrocytic 4R-tau pathology is a key pathological feature of progressive supranuclear palsy (PSP) and other tauopathies, but its contribution to glymphatic dysfunction remains unclear. Here we show that astrocyte-specific 4R-tau overexpression in mice drives aquaporin-4 (AQP4) mislocalization, impairs glymphatic flow, and leads to neurotransmitter dysregulation and parkinsonian-like behavioral deficits. These findings establish a direct link between astrocytic tau pathology, glymphatic impairment, and functional neurological decline, highlighting the glymphatic system as a potential therapeutic target for tauopathies featuring astrocytic 4R-tau pathology, including PSP.
2026-08-11 | Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
2026-08-07 | Molecular Disease Stages of Oligodendrocytic and Neuronal Tau Burden in Progressive Supranuclear Palsy
Abstract Background Progressive supranuclear palsy (PSP) is a primary tauopathy defined by the accumulation of 4R tau isoforms in neurons, oligodendrocytes and astrocytes. Despite evidence of genetic susceptibility operating through glial cell types, it remains poorly understood how cell type-specific epigenetic-transcriptional programs evolve with progression of tau pathology. Methods We conducted single-nucleus chromatin accessibility (snATACseq) and RNA sequencing (snRNAseq) on postmortem frontal cortex samples from PSP patients (n = 8) and matched controls (n = 8), yielding over 144,000 nuclei passing quality control. Tau pathology burden, including neurofibrillary tangles, coiled bodies, and tufted astrocytes, was quantified on AT8-immunostained sections from the same individuals. We integrated differential gene expression analysis, transcription factor motif enrichment, weighted gene co-expression network analysis, and pseudotime modeling anchored to cell type-specific tau pathology burden to delineate molecular pseudo-progression trajectories. Results In eight cell types, 20 subclasses, and 70 subclusters, PSP brains displayed a selective depletion of certain excitatory deep-layer neurons and oligodendrocyte subclusters, with relative preservation of inhibitory neurons and vascular cells. Genetic risk enrichment was localized to astrocytes and oligodendrocytes, whereas excitatory neurons exhibited the greatest transcriptional dysregulation. Oligodendrocyte pseudo-progression indicated a transition from homeostatic myelination programs ( MBP, MOBP ) through glucocorticoid-responsive stress ( FKBP5 , ZBTB16 ), to compensatory myelination ( PLP1, CNP ) and proteostasis stress ( UCHL1, CYRAB, CLU ). Neuronal pseudo- progression revealed early dysregulation of synaptic ( RORB2, NRG3, NPTX1 ), microtubule dynamics ( KIF2C, RAB27B, TUBA/B ), and survival ( MEG3, FTX ) pathways, alongside a transient increase in neuron-glia interactions ( GRIP, CNTNAP4, ERBB4 ), converging late on ribosomal translation and vesicular trafficking modules across all neuronal subtypes. Cross-modal integration with independent cerebrospinal fluid proteomics identified a concordant subset of glial reactivity, axonal injury, and synaptic markers jointly dysregulated in inhibitory neurons, oligodendrocytes, and excitatory deep-layer neurons. Conclusion PSP pathogenesis reflects a combination of glial genetic susceptibility and staged, cell type-specific transcriptional dysfunction. Oligodendrocytes transition from myelination-competent states to FKBP5 -mediated stress states, while neurons show variably timed loss of synaptic excitability and survival programs, preceded by neuron-glia interactions and followed by convergent ribosomal-proteostatic failure. These cytopathology-anchored trajectories outline a potential pathophysiological sequence and may inform candidate selection for stage-specific therapeutic interventions in PSP.
proteins
2026-09-06 | Spectrum of Dystonia in Progressive Supranuclear Palsy: A Prospective Observational Study and Review of Literature.
Dystonia is an under-recognized yet clinically significant feature of Progressive supranuclear palsy (PSP), contributing to disability and impaired motor function. In this prospective study, we examined the clinical and neuroimaging details of eighty-eight consecutive PSP patients who visited our movement disorder clinic [2024-2025]. Patients fulfilling the 2017 Movement Disorder Society-PSP criteria for possible or probable PSP were enrolled after ethics approval and informed consent. We aimed to evaluate the prevalence, phenomenology, subtype associations, clinical and neuroimaging correlates of dystonia. Additionally, a literature search was performed and 29 articles were included for detailed review. The literature review identified predominantly retrospective studies, reporting dystonia in approximately 30-60% of the patients, with variable patterns of cranio-cervical and limb involvement. In our prospective cohort, dystonia was present in 64.8% (n = 57) cases. PSP-RS was the most frequent subtype (39.8%), followed by PSP-P (26.1%) and PSP-CBS (23.8%). Dystonia was more common in PSP-RS and PSP-CBS, with predominant limb dystonia in PSP-CBS, and cranio-cervical dystonia in PSP-RS. A trend toward earlier dystonia was observed in PSP-CBS. Patients with dystonia demonstrated lower Midbrain to pons ratios and higher Magnetic resonance parkinsonism index, suggesting greater brainstem involvement. Botulinum toxin therapy resulted in clinical improvement in selected dystonia patients. Dystonia is a frequent and clinically meaningful feature in PSP. Our prospective study expands upon the existing literature by demonstrating distinct subtype-specific patterns and neuroimaging correlates, supporting the concept of a "dystonia spectrum" in PSP and highlighting its relevance for clinical recognition and management.
2026-07-04 | Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.
Progressive supranuclear palsy (PSP) is a fatal tauopathy presenting an unmet medical need. Davunetide, targeting tauopathy, has been previously tested in PSP, which, when separated by sex, implied efficacy in women. Here, efficacy was evaluated using longitudinal data (52 weeks) and applying for the first time, the US Food and Drug Administration (FDA) -recommended 10-item PSP Rating Scale (PSPRS-10) compared to the 28-item PSPRS (primary endpoint). Time-, sex-, and treatment-related effects were analyzed using linear mixed-effects models including the FDA-recommended Mixed Models for Repeated Measures (MMRM). Cognitive evaluations used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Clinical analyses at the individual level accentuated the impact of the 10 PSPRS chosen items and revealed a significant treatment effect favoring women when accounting for time, sex, and treatment interactions (P = 0.0005). Motor measurements were highlighted. RBANS analyses demonstrated women's significant improvements in total raw score, letter-number sequencing, and language scores. Correlating cerebrospinal fluid (CSF) phosphorylated Tau/Tau with functional outcomes revealed significance with p-Tau/Tau ratio and grasping/imitative/utilizing behavior (assessing involuntary actions in PSPRS-28). This correlation was opposite in direction between females (r = 0.77; P = 0.006) and males (r = -0.62; P = 0.075), with sex difference showing a P = 0.0002 value. Similar results were obtained for language. Predicting the final PSPRS score (week 52), addressing all clinical measures, a clear woman-treatment-specific pattern in outcome importance was discovered, highlighting significance for the primary endpoint Schwab and England Activity of Daily Living (SEADL) scale, and stressing the necessity for sex-specific medicine with davunetide as a lead compound.
2026-06-16 | Tau profiling of brain extracellular vesicles reveals PHF6 peptide as core for pathological tau seeding in Alzheimer's disease.
Tauopathies are neurodegenerative diseases all characterized by tau lesions in the brain. Nevertheless, a clinical and pathophysiological heterogeneity is present among them. This includes the dominant tau isoform found within aggregates (3R and/or 4R tau) along with different brain regions being affected. For some tauopathies, especially in Alzheimer's disease, a specific spatio-temporal staging of tau lesions is present. This staging has been the basis for the prion-like propagation hypothesis, which describes a cell-to-cell transfer of pathological tau species resulting in new aggregates formation in recipient neurons. Human extracellular vesicles isolated from the brain-derived fluid (BD-EVs) of Alzheimer's disease patients contain seeds that contribute to this tau pathology spreading. However, the nature of these tau species responsible for this nucleation activity remains unknown. Additionally, heterogeneity in seeding activity of BD-EVs of Alzheimer's disease, progressive supranuclear palsy and Pick's disease patients is known. Here, EVs were isolated from human frozen tissue (Alzheimer's disease, Progressive Supranuclear Palsy, Pick disease and non-demented controls). We used a tau immunoprecipitation followed by high-resolution mass spectrometry to define their proteomic profile and test their seeding capacity in vitro. We show that the tau profile present within BD-EVs is different among tauopathies. Interestingly, multiple tau peptides located in the microtubule binding region were specifically enriched in Alzheimer's disease extracellular vesicles. Of these, mainly the PHF6 (VQIVYK) containing proteins mediate tau seeding activity. PHF6 is a driver for the higher EVs-mediated tau propagation in AD patients, revealing an interesting therapeutic target to prevent tau pathology spreading.
2026-03-09 | GV1001 reduces pathological 4R tau and functional deficits in models relevant to progressive supranuclear palsy.
GV1001, a peptide drug derived from human telomerase reverse transcriptase, has showed the therapeutic effect in the animal model of Alzheimer’s disease (AD), a representative chronic neurodegenerative disease having impaired learning and memory. In our previous studies, GV1001 has showed the multi-functions including anti-apoptosis, anti-oxidative stress, and anti-neuroinflammation in AD-related in vitro and in vivo systems. Here, in addition to these previously reported functions, GV1001 was discovered to reduce the protein level of 4R tau isoform in the pathological condition. There is no studies providing the potential of GV1001 as a therapeutic drug for neurodegenerative movement disorders. Progressive supranuclear palsy (PSP) is a rare atypical Parkinsonism in the midbrain region, leading to more severe motor symptoms and very rapid pathological progression. Increased 4R tau isoform in an affected brain region of the primary 4R tauopathy is a distinct pathological character in PSP patients. In this study, GV1001 down-regulated the protein level of 4R tau specifically in an annonacin-induced PSP in vitro neuronal model as well as in vivo study using 4R TauP301L-BiFC mouse model. These findings suggest a novel role of GV1001 in 4R tauopathy and support its disease-modifying potential within the context of 4R tau–driven neurodegenerative models, including PSP.
2026-01-11 | Revealing the conformational landscape of tau P → L mutants in R23 tau macromolecule: A pathway to targeted therapeutic design.
Misfolding of the microtubule-associated protein tau is central to the pathology of several neurodegenerative disorders, including Alzheimer's disease, Pick's disease, and progressive supranuclear palsy. Although proline-to-leucine (P → L) substitutions in tau are known to accelerate aggregation, the molecular mechanisms underlying this effect-and potential strategies to counter it-remain incompletely understood. Here, we use replica-exchange molecular dynamics (REMD) to investigate how single (P301L, P332L) and double (P2L) P → L mutations in tau's R23 fragment reshape its conformational landscape. Our simulations reveal that single mutations substantially elevate β-sheet content (by up to 17% compared to wild-type) and increase aggregation propensity. Paradoxically, the double mutant reduces β-sheet formation and enhances α-helical structure, effectively curtailing aggregation. Contact map and hydrogen-bond analysis confirm that introducing the second P → L substitution reorganizes intrachain interactions in a way that mitigates misfolding. These findings advance our fundamental understanding of tau aggregation and suggest a counter-intuitive therapeutic concept: engineering an additional mutation may stabilize tau more effectively than merely suppressing a pathogenic mutation. We propose integrative next steps-virtual screens, AI clustering, and ssNMR-to guide translation.
oligonucleotides
2025-12-01 | From novel targets to potential therapies: development of antisense oligonucleotides for progressive supranuclear palsy
BACKGROUND: Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disorder with rapid progression to death. Multiple efforts to develop a disease-modifying therapy for PSP have yet to succeed. We previously reported the discovery of three potential therapeutic targets for PSP. These three genes, DDR2, KANK2, and STOM, are consistently upregulated in the brains of PSP patients and mouse models of tauopathy. Reducing their expression in a drosophila model significantly rescued the tau-induced eye degeneration and tau seeding activity. To translate these targets into the clinic, we are developing antisense oligonucleotides (ASO) as potential therapies. METHOD: We screened candidate ASOs in neuroglioma cell line H4. ASO hits were validated for their potency and safety. We also used iPSC-derived neurons from PSP patients to test the potency and potential toxicity of our ASOs. To investigate target engagement, therapeutic efficacy and preliminary pharmacodynamic properties, we treated iPSC-derived midbrain organoids with the ASO leads. Lastly, we will assess the off-target effects of the ASOs by investigating the levels of mRNA transcripts that share similar sequences as our targets using RNAseq. RESULT: Our in vitro screening identified ASO leads that significantly reduce the target gene expressions at mRNA and protein levels in a dose-dependent manner. The ASO hits also exhibit low cellular toxicity in the H4 cell line. Upon treating iPSC neurons with ASO hits, we were able to validate the dose-dependent reduction of target mRNAs. Cell viability analysis indicated low toxicity, suggesting that these ASOs are potent and safe. In midbrain organoid model, DDR2-targeting ASO showed time-dependent target engagement and were prioritized for further development. CONCLUSION: We developed candidate therapeutics for PSP using ASOs that silence novel therapeutic targets discovered in our systems based cross-species screening. We showed that our ASOs have low toxicity and confirmed target engagement at both mRNA and protein levels in vitro. The results suggest a favorable preclinical profile of our ASO leads that warrants additional investigations. Importantly, PSP shares congruent pathophysiological changes with other tauopathies, such as Alzheimer's disease. These common perturbed pathways indicate that our ASOs can be potentially repurposed for multiple neurodegenerative tauopathies.
2024-08-14 | Astrocyte tau deposition in progressive supranuclear palsy is associated with dysregulation of MAPT transcription.
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by 4R tau deposition in neurons as well as in astrocytes and oligodendrocytes. While astrocytic tau deposits are rarely observed in normal aging (so-called aging-related tau astrogliopathy, ARTAG) and Alzheimer's disease (AD), astrocytic tau in the form of tufted astrocytes is a pathognomonic hallmark of PSP. Classical biochemical experiments emphasized tau synthesis in neurons in the central nervous system, suggesting that astrocytic tau inclusions might be derived from uptake of extracellular neuronal-derived tau. However, recent single-nucleus RNAseq experiments highlight the fact that MAPT, the gene encoding tau, is also expressed by astrocytes, albeit in lower amounts. We, therefore, revisited the question of whether astrocyte-driven expression of tau might contribute to astrocytic tau aggregates in PSP by performing fluorescent in situ hybridization/immunohistochemical co-localization in human postmortem brain specimens from individuals with PSP and AD with ARTAG as well as normal controls. We find that, in PSP but not in AD, tau-immunoreactive astrocytes have higher levels of MAPT mRNA compared to astrocytes that do not have tau aggregates. These results suggest that astrocytic responses in PSP are unique to this tauopathy and support the possibility that fundamental changes in PSP astrocyte-endogenous mRNA biology contribute to increased synthesis of tau protein and underlies the formation of the astrocytic tau deposits characteristic of PSP.
2024-03-07 | Long non-coding RNA SNHG8 drives stress granule formation in tauopathies.
Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in the MAPT gene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream of MAPT mutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts >200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying a MAPT p.P301L, IVS10 + 16, or p.R406W mutation and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur as a function of the MAPT mutant allele. We identified 15 lncRNAs that were commonly differentially expressed across the three MAPT mutations. The commonly differentially expressed lncRNAs interact with RNA-binding proteins that regulate stress granule formation. Among these lncRNAs, SNHG8 was significantly reduced in a mouse model of tauopathy and in FTLD-tau, progressive supranuclear palsy, and Alzheimer's disease brains. We show that SNHG8 interacts with tau and stress granule-associated RNA-binding protein TIA1. Overexpression of mutant tau in vitro is sufficient to reduce SNHG8 expression and induce stress granule formation. Rescuing SNHG8 expression leads to reduced stress granule formation and reduced TIA1 levels in immortalized cells and in MAPT mutant neurons, suggesting that dysregulation of this non-coding RNA is a causal factor driving stress granule formation via TIA1 in tauopathies.
2023-11-06 | Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy.
Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue (n = 408) and single nucleus RNAseq (n = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM, and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas ( https://rtools.mayo.edu/PSP_RNAseq_Atlas/ ). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases.
2023-08-03 | Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change.
Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer's disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs.
antibodies
2026-03-26 | Distinct neuroinflammatory profiles in progressive supranuclear palsy associated with HLA haplotypes.
Progressive supranuclear palsy is a neurodegenerative four-repeat tauopathy characterized by atypical parkinsonism and cognitive behavioural changes and a relatively uniform neuropathology. Building on prior identification of rare HLA (human leukocyte antigen) haplotypes in progressive supranuclear palsy, this study investigates whether these haplotypes correlate with distinct clinical and immunopathological phenotypes. In addition to retrospective collection of clinical data, we evaluated T and B cells, microglia and phosphorylated-tau (p-Tau) cytopathologies in 32 progressive supranuclear palsy cases. Machine learning was used to analyse whether pathological variables and their ratios, or the sequence of clinical symptoms are different HLA-defined groups, including one linked to narcolepsy (DRB1*15:01-DQB1*06:02). Neuropathology revealed regional differences in the severity of microglia load, density of cytotoxic T cells and p-Tau cytopathologies between groups. Machine learning revealed that specific ratios of neuroinflammatory markers reliably distinguished HLA haplotypes. Additionally, symptom progression sequences varied by HLA haplotype, suggesting a potential effect of neuroinflammatory profiles on disease trajectory. These findings support the notion that progressive supranuclear palsy pathology might be associated with various aetiological-pathogenic events rarely including targetable autoimmune mechanisms as well. The HLA haplotype-dependent diversity of neuroinflammatory markers should be evaluated in clinical and biomarker studies in, and beyond, progressive supranuclear palsy to understand its relevance for patient stratification in disease modifying therapy trials.
2025-10-29 | Neuronal-specific antibody in patients with multiple system atrophy and progressive supranuclear palsy.
Anti-neuronal antibodies can manifest with diverse movement disorders, including parkinsonism and ataxia, and may mimic neurodegeneration. The prevalence of neuronal-specific antibodies in atypical parkinsonism remains unclear. We examined 166 patients, including 136 patients with clinically diagnosed progressive supranuclear palsy (PSP) and 30 patients with multiple system atrophy (MSA) from the Taiwan PSP/CBS Consortium using an integrated set of tissue-based immunofluorescence assays and a subsequent fixed cell-based assay as well as confirmatory tests to detect neuronal-specific antibodies. We observed one PSP-Richardson syndrome patient (0.74 %) was CASPR2-IgG positive, and one MSA-cerebellar subtype patient (3.33 %) showed GAD65 positivity with a hot-cross bun sign on MRI. The latter showed clinical improvement after immunotherapy. Neither patient had sleep-related symptoms. These findings indicate that neuronal-specific antibodies may mimic MSA or PSP and warrant antibody testing in atypical parkinsonism to identify reversible autoimmune causes.
2025-10-08 | Anti-tau VHH therapy against PHF6: a safe approach to slowing the phenotype of tau pathology.
Tauopathies share common features, including tau aggregation, which plays a central role in neurodegeneration. However, these disorders are highly heterogeneous, particularly in the spread of pathological tau species between cells. In Alzheimer's disease, intracellular tau aggregation is followed by a propagation between cells leading to a hierarchical pathway of neurodegeneration, whereas in other tauopathies, such as progressive supranuclear palsy (PSP), pathological tau remains largely confined within neurons and exhibits more limited spread. This variability raises the question of whether tailored treatments for each tauopathy might offer more therapeutic benefit. Hence, we designed two different immunological approaches using single domain antibody fragments, also called VHHs, to target intracellular and extracellular tau. This study aims to first evaluate the safety of these immunological tools on physiological tau and then their potential to slow disease progression. We selected the pro-aggregative tau hexapeptide PHF6 as a common target for the VHHs. These VHHs were cloned in viral vectors allowing to compare two different expression systems: 1) intracytosolic expression to prevent tau accumulation (intraVHH) and 2) secretion into the interstitial fluid, to prevent tau spreading (extraVHH). By stereotactic injection of viral vectors, these VHHs were expressed in the brain of transgenic or wild-type mice and three readouts were studied: behavior, brain imaging and tau lesions. We validated the correct addressing of intra- and extraVHHs. These two constructs were not associated with adverse effects, even in the absence of tau overexpression, in wild-type mice. Their efficacy was demonstrated in transgenic mouse tau models, either chronic long-term or in acute seeding with injections of human brain homogenates from Alzheimer's disease patients. They both can slow down several pathological effects (i.e. cognitive deficits, cerebral atrophy and neuronal hyperphosphorylation of tau). This study is a proof of concept demonstrating that VHHs can be engineered to reduce both intra- and extracellular tau pathologies without major adverse effects, making them of interest for therapeutic applications.
2025-07-21 | Neuroinflammation distinguishes HLA haplotypes in progressive supranuclear palsy
Objectives: Progressive supranuclear palsy (PSP) is a neurodegenerative 4R tauopathy clinically presenting with atypical parkinsonism or cognitive behavioral changes and a relatively uniform neuropathology. We recently identified rare HLA haplotypes in PSP and now examine whether HLA haplotypes are associated with different cytopathological and clinical phenotypes. Methods: Retrospective collection of clinical data and mapping of T and B cells, microglia, and phosphorylated-tau (p-Tau) cytopathologies in 32 PSP cases. Machine learning was used to analyze whether pathological variables and their ratios, or the sequence of clinical symptoms cluster or predict HLA haplotypes. Results: Four groups were defined based on HLA haplotypes: i) 12 cases with the haplotype associated with narcolepsy (DRB1*15:01-DQB1*06:02); ii) 11 cases with other DQ5-DQ6 haplotypes; iii) 8 cases with various haplotypes frequent in the general population; and iv) one case with the haplotype frequent in IgLON5-disease (DRB1*10:01-DQB1*05:01). Neuropathology revealed regional differences in the severity of microglia load, density of cytotoxic T cells, and p-Tau cytopathologies between groups. HLA haplotypes were most distinguishable using machine learned features of inflammatory markers and ratios of neuropathological variables (clustering accuracy: 86.96% and 91.30%, respectively). The sequence of clinical symptoms and the ratios of neuropathological variables were the strongest predictors of HLA haplotypes (prediction accuracy=80.00% and 71.43%, respectively). Interpretation: PSP pathology might be associated with various etiological-pathogenic events including targetable autoimmune mechanisms. The HLA-haplotype dependent diversity of neuroinflammatory markers should be evaluated in clinical and biomarker studies in, and beyond, PSP to understand its relevance for patient stratification in disease modifying therapy trials.
2025-07-07 | Brainstem and cerebellar volume loss and the associated clinical features in Progressive Supranuclear Palsy
Abstract INTRODUCTION Progressive Supranuclear Palsy (PSP) is a neurodegenerative tauopathy. Tau pathology predominates in the basal ganglia and midbrain, with spread to other brain regions. Involvement of the cerebellum remains equivocal, but is increasingly recognized in the pathophysiology of neurological diseases. We hypothesize that volume loss is appreciable in cerebellum alongside brainstem regions. METHODS In this cross-sectional observational study volumetric brainstem and cerebellar subsegmentation of T1-weighted magnetic resonance imaging (MRI) was performed in 37 adults with PSP. Group-level comparisons were made with 38 adults with Parkinson’s disease (PD) and 35 healthy control (HC) subjects. Regional volumes in the PSP cohort were correlated against disease severity and cognition. RESULTS Compared with HC, the midbrain, corpus medullare and flocculonodular lobe were smaller in PSP (d=0.90-1.2). Compared with PD, the midbrain, pons and superior cerebellar peduncle (SCP) were smaller in PSP (d=0.82-1.9). There was a positive correlation between the frontal assessment battery (FAB) and volume of the superior (r=0.50) and inferior (r=0.48) cerebellar posterior lobes. The PSP rating scale also correlated with SCP (r=-0.58) and midbrain (r=-0.52) volume. CONCLUSION Additional regions of brainstem and cerebellar volume loss, alongside midbrain atrophy, were observed in PSP. The reported clinico-radiologic correlations suggest a role of the cerebellum in cognitive dysfunction. These findings indicate that the cerebellum is not spared in PSP, and support further work to understand the temporal course of cerebellar and cerebellar connectivity changes relative to other brain regions.
other
2026-04-22 | Modification of early behavioural, physiological and neuropathological endpoints by syntaxin-6 knockout in a humanised P301S transgenic model of tauopathy.
Genetically mediated increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk mechanism for progressive supranuclear palsy and sporadic prion disease. Increased syntaxin-6 protein levels are also causally associated with Alzheimer's disease, suggesting it may have shared roles across multiple neurodegenerative diseases. However, no study has validated its functional role in tauopathies. To validate a role for syntaxin-6 in tauopathy pathogenesis, we knocked out syntaxin-6 in humanised P301S tauopathy mice. Mice underwent longitudinal rotarod testing, gait analysis, frailty and weight assessment, with neuropathological, biochemical and pathological analyses at 3 and 5 months. Stx6+/+;hTauP301S/P301S mice showed motor impairment from 1 month of age, which was partially rescued by syntaxin-6 knockout from months 1 to 4, with additional protection of gait at 5.5 months. Physiologically, syntaxin-6 knockout exerted a protective effect on weight trajectories and measures of frailty. Reduced neurodegeneration in the superficial cortex was observed at 3 months, as well as higher synaptic coverage at 5 months of age, supporting preserved neuropathological measures related to function. We further observed localised increases in tau pathology in the spinal cord and defined brain regions in young Stx6-/-;hTauP301S/P301S mice, despite total tau levels being comparable, in keeping with altered trafficking of pathological tau species with syntaxin-6 knockout. Despite a partial, early phenotypic rescue of functional measures, terminal endpoint comparisons were confounded by a 20% weight loss culling rule, as knockout mice maintained higher absolute weight. Taken together, this study functionally validates a role for syntaxin-6 in tauopathy pathogenesis, with syntaxin-6 knockout resulting in an early protective effect on multiple disease-relevant phenotypes in a humanised tauopathy model.
2026-03-17 | Natural Killer Subset Changes and Vascular Endothelial Growth Factor-A Plasma Profile in Progressive Supranuclear Palsy: The NKscape Study.
Emerging evidence implicates neuroinflammation in progressive supranuclear palsy (PSP) pathophysiology, with elevated cyto-chemokines suggesting natural killer (NK) cell involvement. We characterized peripheral NK in PSP (N = 11) versus Parkinson's disease (PD, N = 10) and healthy controls (HC, N = 8) at both immunophenotypic and transcriptional levels. PSP patients showed significantly reduced CD3-CD56 + NK frequency (1.35% ± 0.98%) compared with HC (2.96% ± 1.14%) and PD (2.03% ± 0.86%), specifically affecting the immunoregulatory CD56brightCD16-/dim subset. PSP NK cells exhibited elevated CX3CR1 expression, suggesting enhanced migratory capacity toward inflamed tissues. Transcriptomic analysis of primary NK cells revealed 208 DEG with significant enrichment in angiogenesis pathways, particularly vascular endothelial growth factor-A (VEGF-A). Plasma VEGF-A measurements demonstrated a disease-specific pattern: inverse correlation with severity in PSP versus direct correlation in PD. These findings identify a potentially disease-specific transcriptional signature with repercussions on the cyto-chemokine plasma profile. Further investigation of the NK cell-mediated immune response in PSP may provide new insights into disease mechanisms and open avenues for immunomodulatory therapeutic strategies. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2025-06-13 | The potential of proteomics for in-depth molecular investigations of progressive supranuclear palsy.
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder. The lack of comprehension about the pathogenesis of the disease, its heterogeneity, and the complex clinical evaluation in early stages, limit the development of effective treatments for PSP patients and highlight the need of further research on the field. In this work, we review the current knowledge of the physio- and neuropathology of PSP, its clinical features, diagnosis markers, and treatment options. We also compare the proteomic-based studies done to date in brain tissues as well as in cerebrospinal fluid and other non-cerebral samples, briefly describing the proteomic approach used and the biological findings obtained in each study. PSP is a complex neurodegenerative disorder marked by tau aggregation, glial dysfunction, and neuroinflammation. Although advances in neuroimaging and biofluid biomarkers have improved PSP diagnostic accuracy, no disease-modifying therapies are currently available. Promising avenues such as tau PET tracers, seed amplification assays, and advanced proteomic-based approaches are enhancing our ability to detect disease-specific tau pathology and hold the potential to provide novel biomarkers for earlier and more precise clinical diagnosis and treatment development that could transform the landscape of PSP.
2025-01-30 | Sensitive detection and propagation of brain-derived tau assemblies in HEK293-based wild-type tau seeding assays.
The assembly of tau into filaments defines tauopathies, a group of neurodegenerative diseases including Alzheimer's disease (AD), Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). The seeded aggregation of tau has been modeled in cell culture using pro-aggregate modifications such as truncation of N- and C-termini and point mutations within the microtubule-binding repeat domain. This limits the applicability of research findings to sporadic disease, where aggregates contain wild-type, full-length tau. We describe a sensitive and specific biosensor assays for brain-derived tau species utilizing wild-type 0N3R and 0N4R tau expressed in HEK293 cells. We further generate a cell line that propagates AD-templated insoluble tau which is hyperphosphorylated at disease-relevant sites and retains a seeding profile similar to AD. We propose these systems as an advance over existing cell-based seeding assays, as they display specificity to the conformation and isoform composition of sporadic human disease.
2025-01-20 | Idiopathic normal pressure hydrocephalus concomitant with progressive supranuclear palsy.
Recent studies by us and others have unveiled a frequent coexistence of idiopathic normal pressure hydrocephalus (iNPH) with neurodegenerative movement disorders, including progressive supranuclear palsy (PSP). This study aims to explore the clinical and radiological characteristics of patients with iNPH who also had comorbid with PSP, referred to as iNPHc + PSP. We retrospectively analyzed patients with iNPH admitted to our department between 2009 and 2024. We adhered to the established clinical criteria for iNPH and the Movement Disorder Society (MDS)-PSP criteria for probable or possible PSP with minor modifications. Among 85 iNPH patients, 18 were categorized as having iNPHc + PSP (21.2 %). Clinically, comorbid PSP led to impaired vertical eye movement, axial-dominant parkinsonism, and a propensity to fall backward in iNPH (p = 0.022, p = 0.002, and p < 0.005, respectively). Radiologically, comorbid PSP demonstrated a shortened mesencephalic tegmentum length in the magnetic resonance imaging and an asymmetrical deficit of dopamine transporter activities in the DaTscan (p = 0.0005, p = 0.0129, respectively). Lumboperitoneal shunt (LPS) surgery improved the modified Rankin scale (p = 0.038) and the iNPH grading scale (total score, p = 0.003; gait disturbance, p = 0.020; urinary incontinence, p = 0.026) one-year after surgery. PSP can coexist with iNPH, and detailed clinical and radiological assessment can aid in detecting this comorbidity. Importantly, LPS surgery can improve outcomes of patients with iNPHc + PSP.
small molecules
2026-09-03 | Elevated DYRK1A in Primary Tauopathies and Therapeutic Targeting with the Brain-Penetrant Inhibitor DYR533.
Neurodegenerative disorders are increasing in prevalence, yet disease-modifying therapies remain limited. Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) phosphorylates tau and regulates inflammatory signaling, making it a potential therapeutic target for neurodegenerative diseases. To investigate the relevance of DYRK1A to primary tauopathies, we first evaluated DYRK1A protein levels in the superior frontal gyrus of individuals with Pick's disease, corticobasal degeneration, and progressive supranuclear palsy. DYRK1A protein expression was significantly elevated in individuals with primary tauopathies compared with healthy controls and positively correlated with Braak stage. Conversely, DYRK1A levels inversely correlated with last Mini-Mental State Examination (MMSE) scores and brain weight, linking elevated DYRK1A expression to disease severity. We next developed DYR533, a selective, orally bioavailable, brain-penetrant small-molecule DYRK1A inhibitor with an S(35) score of 1.4 nM based on a 403-target KINOMEscan assay. Mechanistically, DYR533 prevented the autophosphorylation of newly translated DYRK1A, rendering the kinase inactive and thereby inhibiting phosphorylation of downstream substrates. We next evaluated the therapeutic efficacy of DYR533 in the PS19 mouse model of primary tauopathy, assessing tau hyperphosphorylation, neuroinflammation, motor function, and spatial cognition. DYR533 reduced tau hyperphosphorylation at threonine 217, threonine 181, and serine 396, and attenuated the expression of neuroinflammatory cytokines and chemokines implicated in disease progression. In PS19 mice, DYR533 treatment produced modest improvements on behavior. Together, these findings establish an association between elevated DYRK1A and disease severity in human primary tauopathies and demonstrate that pharmacological inhibition of DYRK1A with DYR533 reduces pathological tau phosphorylation and neuroinflammatory signaling in vivo.
2026-08-21 | Phase 2a Randomized Controlled Trial of TPN-101, A Nucleoside Reverse Transcriptase Inhibitor, in Progressive Supranuclear Palsy.
Preclinical and human brain postmortem studies indicate that progressive supranuclear palsy (PSP) is associated with increased expression of the retrotransposon Long Interspersed Nuclear Element-1 (L1Hs). L1Hs activity initiates an innate immune response that leads to neuroinflammation and neurodegeneration, which can be attenuated by inhibiting the L1Hs-encoded reverse transcriptase. TPN-101 is a potent inhibitor of the L1Hs reverse transcriptase. The objective of this study was to assess the safety, pharmacokinetics, and biomarker and clinical effects of TPN-101 in patients with PSP. A double-blind, placebo-controlled, parallel-group study randomly assigned patients with probable PSP to receive TPN-101 100, 200, or 400 mg, or placebo daily for 24 weeks. Following the double-blind period, all patients received open-label TPN-101 400 mg daily for 24 weeks. The primary outcome was the incidence and severity of treatment-emergent adverse events. Biomarker, clinical, and TPN-101 pharmacokinetic assessments were conducted throughout the study. Forty-two patients were randomly assigned to TPN-101 100 mg (N = 11), 200 mg (N = 10), 400 mg (N = 11), or placebo (N = 10). TPN-101 was well tolerated, with no notable safety differences between any drug dose and placebo. Greater reductions in cerebrospinal fluid levels of neurofilament light chain with increasing dose were seen in patients taking TPN-101 during the double-blind period, compared with an increase in the placebo arm. There were no differences among the treatments on the Progressive Supranuclear Palsy Rating Scale during the double-blind period. The safety, pharmacokinetics, and reductions in biomarkers of neuroinflammation and neurodegeneration warrant future trials powered to detect clinical effects of TPN-101 in PSP. © 2026 International Parkinson and Movement Disorder Society.
2026-08-19 | Astrocytic 4R-tau pathology drives aquaporin-4 (AQP4) mislocalization, glymphatic dysfunction, and neurotransmitter dysregulation in mice.
Progressive supranuclear palsy (PSP) is a severe neurodegenerative tauopathy defined by astrocytic tau inclusions and parkinsonism. The link between astrogliopathy and compromised cerebral fluid dynamics remains unclear. We generated a glial fibrillary acidic protein (GFAP)-e (2A-mMAPT(4R) cDNA) transgenic mouse model (GFAP/tau Tg) with astrocyte-specific expression of 4-repeat (4R) tau to investigate mechanisms underlying astrocytic tau pathology as seen in PSP. Both male and female mice were used in this study. GFAP/tau Tg mice exhibited robust astrocytic hyperphosphorylated tau (p-tau) deposition and activation. Mechanistically, this pathology caused dysregulation of the dystrophin-associated complex (DAC), leading to a critical loss of Aquaporin 4 (AQP4) polarity and aberrant AQP4 distribution in perivascular endfeet. This DAC-AQP4 axis disruption critically impaired cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, subsequently causing deficient glymphatic fluid drainage and excessive ISF accumulation. This fluid stasis was correlated with a significant decline in the synaptic neurotransmitters dopamine (DA) and acetylcholine (ACh). Ultimately, these pathological events manifested as parkinsonian-like motor dysfunction and cognitive deficits in the transgenic mice. Our study clarifies a novel, sequential mechanism linking astrocytic 4R tauopathy to glymphatic circulation failure and neurochemical deficits that recapitulates key astroglial pathological features of PSP. These findings establish the glymphatic system as a compelling therapeutic target for treating neurodegenerative disorders linked to astrogliopathy.Significance Statement Astrocytic 4R-tau pathology is a key pathological feature of progressive supranuclear palsy (PSP) and other tauopathies, but its contribution to glymphatic dysfunction remains unclear. Here we show that astrocyte-specific 4R-tau overexpression in mice drives aquaporin-4 (AQP4) mislocalization, impairs glymphatic flow, and leads to neurotransmitter dysregulation and parkinsonian-like behavioral deficits. These findings establish a direct link between astrocytic tau pathology, glymphatic impairment, and functional neurological decline, highlighting the glymphatic system as a potential therapeutic target for tauopathies featuring astrocytic 4R-tau pathology, including PSP.
2026-08-11 | Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study.
Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm. Further coupled with sex-dependent transcriptional control, ADNP/davunetide cytoplasmic microtubule/Tau targeting is translated into differential sex regulation of key cellular processes including neurogenesis, synaptic function, and axonal transport, then decoded into sexual dichotomy in multicellular processes directing sex-dependent behavioral outcomes. ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes.
2026-08-07 | Molecular Disease Stages of Oligodendrocytic and Neuronal Tau Burden in Progressive Supranuclear Palsy
Abstract Background Progressive supranuclear palsy (PSP) is a primary tauopathy defined by the accumulation of 4R tau isoforms in neurons, oligodendrocytes and astrocytes. Despite evidence of genetic susceptibility operating through glial cell types, it remains poorly understood how cell type-specific epigenetic-transcriptional programs evolve with progression of tau pathology. Methods We conducted single-nucleus chromatin accessibility (snATACseq) and RNA sequencing (snRNAseq) on postmortem frontal cortex samples from PSP patients (n = 8) and matched controls (n = 8), yielding over 144,000 nuclei passing quality control. Tau pathology burden, including neurofibrillary tangles, coiled bodies, and tufted astrocytes, was quantified on AT8-immunostained sections from the same individuals. We integrated differential gene expression analysis, transcription factor motif enrichment, weighted gene co-expression network analysis, and pseudotime modeling anchored to cell type-specific tau pathology burden to delineate molecular pseudo-progression trajectories. Results In eight cell types, 20 subclasses, and 70 subclusters, PSP brains displayed a selective depletion of certain excitatory deep-layer neurons and oligodendrocyte subclusters, with relative preservation of inhibitory neurons and vascular cells. Genetic risk enrichment was localized to astrocytes and oligodendrocytes, whereas excitatory neurons exhibited the greatest transcriptional dysregulation. Oligodendrocyte pseudo-progression indicated a transition from homeostatic myelination programs ( MBP, MOBP ) through glucocorticoid-responsive stress ( FKBP5 , ZBTB16 ), to compensatory myelination ( PLP1, CNP ) and proteostasis stress ( UCHL1, CYRAB, CLU ). Neuronal pseudo- progression revealed early dysregulation of synaptic ( RORB2, NRG3, NPTX1 ), microtubule dynamics ( KIF2C, RAB27B, TUBA/B ), and survival ( MEG3, FTX ) pathways, alongside a transient increase in neuron-glia interactions ( GRIP, CNTNAP4, ERBB4 ), converging late on ribosomal translation and vesicular trafficking modules across all neuronal subtypes. Cross-modal integration with independent cerebrospinal fluid proteomics identified a concordant subset of glial reactivity, axonal injury, and synaptic markers jointly dysregulated in inhibitory neurons, oligodendrocytes, and excitatory deep-layer neurons. Conclusion PSP pathogenesis reflects a combination of glial genetic susceptibility and staged, cell type-specific transcriptional dysfunction. Oligodendrocytes transition from myelination-competent states to FKBP5 -mediated stress states, while neurons show variably timed loss of synaptic excitability and survival programs, preceded by neuron-glia interactions and followed by convergent ribosomal-proteostatic failure. These cytopathology-anchored trajectories outline a potential pathophysiological sequence and may inform candidate selection for stage-specific therapeutic interventions in PSP.
proteins
2026-09-06 | Spectrum of Dystonia in Progressive Supranuclear Palsy: A Prospective Observational Study and Review of Literature.
Dystonia is an under-recognized yet clinically significant feature of Progressive supranuclear palsy (PSP), contributing to disability and impaired motor function. In this prospective study, we examined the clinical and neuroimaging details of eighty-eight consecutive PSP patients who visited our movement disorder clinic [2024-2025]. Patients fulfilling the 2017 Movement Disorder Society-PSP criteria for possible or probable PSP were enrolled after ethics approval and informed consent. We aimed to evaluate the prevalence, phenomenology, subtype associations, clinical and neuroimaging correlates of dystonia. Additionally, a literature search was performed and 29 articles were included for detailed review. The literature review identified predominantly retrospective studies, reporting dystonia in approximately 30-60% of the patients, with variable patterns of cranio-cervical and limb involvement. In our prospective cohort, dystonia was present in 64.8% (n = 57) cases. PSP-RS was the most frequent subtype (39.8%), followed by PSP-P (26.1%) and PSP-CBS (23.8%). Dystonia was more common in PSP-RS and PSP-CBS, with predominant limb dystonia in PSP-CBS, and cranio-cervical dystonia in PSP-RS. A trend toward earlier dystonia was observed in PSP-CBS. Patients with dystonia demonstrated lower Midbrain to pons ratios and higher Magnetic resonance parkinsonism index, suggesting greater brainstem involvement. Botulinum toxin therapy resulted in clinical improvement in selected dystonia patients. Dystonia is a frequent and clinically meaningful feature in PSP. Our prospective study expands upon the existing literature by demonstrating distinct subtype-specific patterns and neuroimaging correlates, supporting the concept of a "dystonia spectrum" in PSP and highlighting its relevance for clinical recognition and management.
2026-07-04 | Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.
Progressive supranuclear palsy (PSP) is a fatal tauopathy presenting an unmet medical need. Davunetide, targeting tauopathy, has been previously tested in PSP, which, when separated by sex, implied efficacy in women. Here, efficacy was evaluated using longitudinal data (52 weeks) and applying for the first time, the US Food and Drug Administration (FDA) -recommended 10-item PSP Rating Scale (PSPRS-10) compared to the 28-item PSPRS (primary endpoint). Time-, sex-, and treatment-related effects were analyzed using linear mixed-effects models including the FDA-recommended Mixed Models for Repeated Measures (MMRM). Cognitive evaluations used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Clinical analyses at the individual level accentuated the impact of the 10 PSPRS chosen items and revealed a significant treatment effect favoring women when accounting for time, sex, and treatment interactions (P = 0.0005). Motor measurements were highlighted. RBANS analyses demonstrated women's significant improvements in total raw score, letter-number sequencing, and language scores. Correlating cerebrospinal fluid (CSF) phosphorylated Tau/Tau with functional outcomes revealed significance with p-Tau/Tau ratio and grasping/imitative/utilizing behavior (assessing involuntary actions in PSPRS-28). This correlation was opposite in direction between females (r = 0.77; P = 0.006) and males (r = -0.62; P = 0.075), with sex difference showing a P = 0.0002 value. Similar results were obtained for language. Predicting the final PSPRS score (week 52), addressing all clinical measures, a clear woman-treatment-specific pattern in outcome importance was discovered, highlighting significance for the primary endpoint Schwab and England Activity of Daily Living (SEADL) scale, and stressing the necessity for sex-specific medicine with davunetide as a lead compound.
2026-06-16 | Tau profiling of brain extracellular vesicles reveals PHF6 peptide as core for pathological tau seeding in Alzheimer's disease.
Tauopathies are neurodegenerative diseases all characterized by tau lesions in the brain. Nevertheless, a clinical and pathophysiological heterogeneity is present among them. This includes the dominant tau isoform found within aggregates (3R and/or 4R tau) along with different brain regions being affected. For some tauopathies, especially in Alzheimer's disease, a specific spatio-temporal staging of tau lesions is present. This staging has been the basis for the prion-like propagation hypothesis, which describes a cell-to-cell transfer of pathological tau species resulting in new aggregates formation in recipient neurons. Human extracellular vesicles isolated from the brain-derived fluid (BD-EVs) of Alzheimer's disease patients contain seeds that contribute to this tau pathology spreading. However, the nature of these tau species responsible for this nucleation activity remains unknown. Additionally, heterogeneity in seeding activity of BD-EVs of Alzheimer's disease, progressive supranuclear palsy and Pick's disease patients is known. Here, EVs were isolated from human frozen tissue (Alzheimer's disease, Progressive Supranuclear Palsy, Pick disease and non-demented controls). We used a tau immunoprecipitation followed by high-resolution mass spectrometry to define their proteomic profile and test their seeding capacity in vitro. We show that the tau profile present within BD-EVs is different among tauopathies. Interestingly, multiple tau peptides located in the microtubule binding region were specifically enriched in Alzheimer's disease extracellular vesicles. Of these, mainly the PHF6 (VQIVYK) containing proteins mediate tau seeding activity. PHF6 is a driver for the higher EVs-mediated tau propagation in AD patients, revealing an interesting therapeutic target to prevent tau pathology spreading.
2026-03-09 | GV1001 reduces pathological 4R tau and functional deficits in models relevant to progressive supranuclear palsy.
GV1001, a peptide drug derived from human telomerase reverse transcriptase, has showed the therapeutic effect in the animal model of Alzheimer’s disease (AD), a representative chronic neurodegenerative disease having impaired learning and memory. In our previous studies, GV1001 has showed the multi-functions including anti-apoptosis, anti-oxidative stress, and anti-neuroinflammation in AD-related in vitro and in vivo systems. Here, in addition to these previously reported functions, GV1001 was discovered to reduce the protein level of 4R tau isoform in the pathological condition. There is no studies providing the potential of GV1001 as a therapeutic drug for neurodegenerative movement disorders. Progressive supranuclear palsy (PSP) is a rare atypical Parkinsonism in the midbrain region, leading to more severe motor symptoms and very rapid pathological progression. Increased 4R tau isoform in an affected brain region of the primary 4R tauopathy is a distinct pathological character in PSP patients. In this study, GV1001 down-regulated the protein level of 4R tau specifically in an annonacin-induced PSP in vitro neuronal model as well as in vivo study using 4R TauP301L-BiFC mouse model. These findings suggest a novel role of GV1001 in 4R tauopathy and support its disease-modifying potential within the context of 4R tau–driven neurodegenerative models, including PSP.
2026-01-11 | Revealing the conformational landscape of tau P → L mutants in R23 tau macromolecule: A pathway to targeted therapeutic design.
Misfolding of the microtubule-associated protein tau is central to the pathology of several neurodegenerative disorders, including Alzheimer's disease, Pick's disease, and progressive supranuclear palsy. Although proline-to-leucine (P → L) substitutions in tau are known to accelerate aggregation, the molecular mechanisms underlying this effect-and potential strategies to counter it-remain incompletely understood. Here, we use replica-exchange molecular dynamics (REMD) to investigate how single (P301L, P332L) and double (P2L) P → L mutations in tau's R23 fragment reshape its conformational landscape. Our simulations reveal that single mutations substantially elevate β-sheet content (by up to 17% compared to wild-type) and increase aggregation propensity. Paradoxically, the double mutant reduces β-sheet formation and enhances α-helical structure, effectively curtailing aggregation. Contact map and hydrogen-bond analysis confirm that introducing the second P → L substitution reorganizes intrachain interactions in a way that mitigates misfolding. These findings advance our fundamental understanding of tau aggregation and suggest a counter-intuitive therapeutic concept: engineering an additional mutation may stabilize tau more effectively than merely suppressing a pathogenic mutation. We propose integrative next steps-virtual screens, AI clustering, and ssNMR-to guide translation.
oligonucleotides
2025-12-01 | From novel targets to potential therapies: development of antisense oligonucleotides for progressive supranuclear palsy
BACKGROUND: Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disorder with rapid progression to death. Multiple efforts to develop a disease-modifying therapy for PSP have yet to succeed. We previously reported the discovery of three potential therapeutic targets for PSP. These three genes, DDR2, KANK2, and STOM, are consistently upregulated in the brains of PSP patients and mouse models of tauopathy. Reducing their expression in a drosophila model significantly rescued the tau-induced eye degeneration and tau seeding activity. To translate these targets into the clinic, we are developing antisense oligonucleotides (ASO) as potential therapies. METHOD: We screened candidate ASOs in neuroglioma cell line H4. ASO hits were validated for their potency and safety. We also used iPSC-derived neurons from PSP patients to test the potency and potential toxicity of our ASOs. To investigate target engagement, therapeutic efficacy and preliminary pharmacodynamic properties, we treated iPSC-derived midbrain organoids with the ASO leads. Lastly, we will assess the off-target effects of the ASOs by investigating the levels of mRNA transcripts that share similar sequences as our targets using RNAseq. RESULT: Our in vitro screening identified ASO leads that significantly reduce the target gene expressions at mRNA and protein levels in a dose-dependent manner. The ASO hits also exhibit low cellular toxicity in the H4 cell line. Upon treating iPSC neurons with ASO hits, we were able to validate the dose-dependent reduction of target mRNAs. Cell viability analysis indicated low toxicity, suggesting that these ASOs are potent and safe. In midbrain organoid model, DDR2-targeting ASO showed time-dependent target engagement and were prioritized for further development. CONCLUSION: We developed candidate therapeutics for PSP using ASOs that silence novel therapeutic targets discovered in our systems based cross-species screening. We showed that our ASOs have low toxicity and confirmed target engagement at both mRNA and protein levels in vitro. The results suggest a favorable preclinical profile of our ASO leads that warrants additional investigations. Importantly, PSP shares congruent pathophysiological changes with other tauopathies, such as Alzheimer's disease. These common perturbed pathways indicate that our ASOs can be potentially repurposed for multiple neurodegenerative tauopathies.
2024-08-14 | Astrocyte tau deposition in progressive supranuclear palsy is associated with dysregulation of MAPT transcription.
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by 4R tau deposition in neurons as well as in astrocytes and oligodendrocytes. While astrocytic tau deposits are rarely observed in normal aging (so-called aging-related tau astrogliopathy, ARTAG) and Alzheimer's disease (AD), astrocytic tau in the form of tufted astrocytes is a pathognomonic hallmark of PSP. Classical biochemical experiments emphasized tau synthesis in neurons in the central nervous system, suggesting that astrocytic tau inclusions might be derived from uptake of extracellular neuronal-derived tau. However, recent single-nucleus RNAseq experiments highlight the fact that MAPT, the gene encoding tau, is also expressed by astrocytes, albeit in lower amounts. We, therefore, revisited the question of whether astrocyte-driven expression of tau might contribute to astrocytic tau aggregates in PSP by performing fluorescent in situ hybridization/immunohistochemical co-localization in human postmortem brain specimens from individuals with PSP and AD with ARTAG as well as normal controls. We find that, in PSP but not in AD, tau-immunoreactive astrocytes have higher levels of MAPT mRNA compared to astrocytes that do not have tau aggregates. These results suggest that astrocytic responses in PSP are unique to this tauopathy and support the possibility that fundamental changes in PSP astrocyte-endogenous mRNA biology contribute to increased synthesis of tau protein and underlies the formation of the astrocytic tau deposits characteristic of PSP.
2024-03-07 | Long non-coding RNA SNHG8 drives stress granule formation in tauopathies.
Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in the MAPT gene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream of MAPT mutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts >200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying a MAPT p.P301L, IVS10 + 16, or p.R406W mutation and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur as a function of the MAPT mutant allele. We identified 15 lncRNAs that were commonly differentially expressed across the three MAPT mutations. The commonly differentially expressed lncRNAs interact with RNA-binding proteins that regulate stress granule formation. Among these lncRNAs, SNHG8 was significantly reduced in a mouse model of tauopathy and in FTLD-tau, progressive supranuclear palsy, and Alzheimer's disease brains. We show that SNHG8 interacts with tau and stress granule-associated RNA-binding protein TIA1. Overexpression of mutant tau in vitro is sufficient to reduce SNHG8 expression and induce stress granule formation. Rescuing SNHG8 expression leads to reduced stress granule formation and reduced TIA1 levels in immortalized cells and in MAPT mutant neurons, suggesting that dysregulation of this non-coding RNA is a causal factor driving stress granule formation via TIA1 in tauopathies.
2023-11-06 | Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy.
Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue (n = 408) and single nucleus RNAseq (n = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM, and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas ( https://rtools.mayo.edu/PSP_RNAseq_Atlas/ ). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases.
2023-08-03 | Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change.
Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer's disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs.
antibodies
2026-03-26 | Distinct neuroinflammatory profiles in progressive supranuclear palsy associated with HLA haplotypes.
Progressive supranuclear palsy is a neurodegenerative four-repeat tauopathy characterized by atypical parkinsonism and cognitive behavioural changes and a relatively uniform neuropathology. Building on prior identification of rare HLA (human leukocyte antigen) haplotypes in progressive supranuclear palsy, this study investigates whether these haplotypes correlate with distinct clinical and immunopathological phenotypes. In addition to retrospective collection of clinical data, we evaluated T and B cells, microglia and phosphorylated-tau (p-Tau) cytopathologies in 32 progressive supranuclear palsy cases. Machine learning was used to analyse whether pathological variables and their ratios, or the sequence of clinical symptoms are different HLA-defined groups, including one linked to narcolepsy (DRB1*15:01-DQB1*06:02). Neuropathology revealed regional differences in the severity of microglia load, density of cytotoxic T cells and p-Tau cytopathologies between groups. Machine learning revealed that specific ratios of neuroinflammatory markers reliably distinguished HLA haplotypes. Additionally, symptom progression sequences varied by HLA haplotype, suggesting a potential effect of neuroinflammatory profiles on disease trajectory. These findings support the notion that progressive supranuclear palsy pathology might be associated with various aetiological-pathogenic events rarely including targetable autoimmune mechanisms as well. The HLA haplotype-dependent diversity of neuroinflammatory markers should be evaluated in clinical and biomarker studies in, and beyond, progressive supranuclear palsy to understand its relevance for patient stratification in disease modifying therapy trials.
2025-10-29 | Neuronal-specific antibody in patients with multiple system atrophy and progressive supranuclear palsy.
Anti-neuronal antibodies can manifest with diverse movement disorders, including parkinsonism and ataxia, and may mimic neurodegeneration. The prevalence of neuronal-specific antibodies in atypical parkinsonism remains unclear. We examined 166 patients, including 136 patients with clinically diagnosed progressive supranuclear palsy (PSP) and 30 patients with multiple system atrophy (MSA) from the Taiwan PSP/CBS Consortium using an integrated set of tissue-based immunofluorescence assays and a subsequent fixed cell-based assay as well as confirmatory tests to detect neuronal-specific antibodies. We observed one PSP-Richardson syndrome patient (0.74 %) was CASPR2-IgG positive, and one MSA-cerebellar subtype patient (3.33 %) showed GAD65 positivity with a hot-cross bun sign on MRI. The latter showed clinical improvement after immunotherapy. Neither patient had sleep-related symptoms. These findings indicate that neuronal-specific antibodies may mimic MSA or PSP and warrant antibody testing in atypical parkinsonism to identify reversible autoimmune causes.
2025-10-08 | Anti-tau VHH therapy against PHF6: a safe approach to slowing the phenotype of tau pathology.
Tauopathies share common features, including tau aggregation, which plays a central role in neurodegeneration. However, these disorders are highly heterogeneous, particularly in the spread of pathological tau species between cells. In Alzheimer's disease, intracellular tau aggregation is followed by a propagation between cells leading to a hierarchical pathway of neurodegeneration, whereas in other tauopathies, such as progressive supranuclear palsy (PSP), pathological tau remains largely confined within neurons and exhibits more limited spread. This variability raises the question of whether tailored treatments for each tauopathy might offer more therapeutic benefit. Hence, we designed two different immunological approaches using single domain antibody fragments, also called VHHs, to target intracellular and extracellular tau. This study aims to first evaluate the safety of these immunological tools on physiological tau and then their potential to slow disease progression. We selected the pro-aggregative tau hexapeptide PHF6 as a common target for the VHHs. These VHHs were cloned in viral vectors allowing to compare two different expression systems: 1) intracytosolic expression to prevent tau accumulation (intraVHH) and 2) secretion into the interstitial fluid, to prevent tau spreading (extraVHH). By stereotactic injection of viral vectors, these VHHs were expressed in the brain of transgenic or wild-type mice and three readouts were studied: behavior, brain imaging and tau lesions. We validated the correct addressing of intra- and extraVHHs. These two constructs were not associated with adverse effects, even in the absence of tau overexpression, in wild-type mice. Their efficacy was demonstrated in transgenic mouse tau models, either chronic long-term or in acute seeding with injections of human brain homogenates from Alzheimer's disease patients. They both can slow down several pathological effects (i.e. cognitive deficits, cerebral atrophy and neuronal hyperphosphorylation of tau). This study is a proof of concept demonstrating that VHHs can be engineered to reduce both intra- and extracellular tau pathologies without major adverse effects, making them of interest for therapeutic applications.
2025-07-21 | Neuroinflammation distinguishes HLA haplotypes in progressive supranuclear palsy
Objectives: Progressive supranuclear palsy (PSP) is a neurodegenerative 4R tauopathy clinically presenting with atypical parkinsonism or cognitive behavioral changes and a relatively uniform neuropathology. We recently identified rare HLA haplotypes in PSP and now examine whether HLA haplotypes are associated with different cytopathological and clinical phenotypes. Methods: Retrospective collection of clinical data and mapping of T and B cells, microglia, and phosphorylated-tau (p-Tau) cytopathologies in 32 PSP cases. Machine learning was used to analyze whether pathological variables and their ratios, or the sequence of clinical symptoms cluster or predict HLA haplotypes. Results: Four groups were defined based on HLA haplotypes: i) 12 cases with the haplotype associated with narcolepsy (DRB1*15:01-DQB1*06:02); ii) 11 cases with other DQ5-DQ6 haplotypes; iii) 8 cases with various haplotypes frequent in the general population; and iv) one case with the haplotype frequent in IgLON5-disease (DRB1*10:01-DQB1*05:01). Neuropathology revealed regional differences in the severity of microglia load, density of cytotoxic T cells, and p-Tau cytopathologies between groups. HLA haplotypes were most distinguishable using machine learned features of inflammatory markers and ratios of neuropathological variables (clustering accuracy: 86.96% and 91.30%, respectively). The sequence of clinical symptoms and the ratios of neuropathological variables were the strongest predictors of HLA haplotypes (prediction accuracy=80.00% and 71.43%, respectively). Interpretation: PSP pathology might be associated with various etiological-pathogenic events including targetable autoimmune mechanisms. The HLA-haplotype dependent diversity of neuroinflammatory markers should be evaluated in clinical and biomarker studies in, and beyond, PSP to understand its relevance for patient stratification in disease modifying therapy trials.
2025-07-07 | Brainstem and cerebellar volume loss and the associated clinical features in Progressive Supranuclear Palsy
Abstract INTRODUCTION Progressive Supranuclear Palsy (PSP) is a neurodegenerative tauopathy. Tau pathology predominates in the basal ganglia and midbrain, with spread to other brain regions. Involvement of the cerebellum remains equivocal, but is increasingly recognized in the pathophysiology of neurological diseases. We hypothesize that volume loss is appreciable in cerebellum alongside brainstem regions. METHODS In this cross-sectional observational study volumetric brainstem and cerebellar subsegmentation of T1-weighted magnetic resonance imaging (MRI) was performed in 37 adults with PSP. Group-level comparisons were made with 38 adults with Parkinson’s disease (PD) and 35 healthy control (HC) subjects. Regional volumes in the PSP cohort were correlated against disease severity and cognition. RESULTS Compared with HC, the midbrain, corpus medullare and flocculonodular lobe were smaller in PSP (d=0.90-1.2). Compared with PD, the midbrain, pons and superior cerebellar peduncle (SCP) were smaller in PSP (d=0.82-1.9). There was a positive correlation between the frontal assessment battery (FAB) and volume of the superior (r=0.50) and inferior (r=0.48) cerebellar posterior lobes. The PSP rating scale also correlated with SCP (r=-0.58) and midbrain (r=-0.52) volume. CONCLUSION Additional regions of brainstem and cerebellar volume loss, alongside midbrain atrophy, were observed in PSP. The reported clinico-radiologic correlations suggest a role of the cerebellum in cognitive dysfunction. These findings indicate that the cerebellum is not spared in PSP, and support further work to understand the temporal course of cerebellar and cerebellar connectivity changes relative to other brain regions.
other
2026-04-22 | Modification of early behavioural, physiological and neuropathological endpoints by syntaxin-6 knockout in a humanised P301S transgenic model of tauopathy.
Genetically mediated increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk mechanism for progressive supranuclear palsy and sporadic prion disease. Increased syntaxin-6 protein levels are also causally associated with Alzheimer's disease, suggesting it may have shared roles across multiple neurodegenerative diseases. However, no study has validated its functional role in tauopathies. To validate a role for syntaxin-6 in tauopathy pathogenesis, we knocked out syntaxin-6 in humanised P301S tauopathy mice. Mice underwent longitudinal rotarod testing, gait analysis, frailty and weight assessment, with neuropathological, biochemical and pathological analyses at 3 and 5 months. Stx6+/+;hTauP301S/P301S mice showed motor impairment from 1 month of age, which was partially rescued by syntaxin-6 knockout from months 1 to 4, with additional protection of gait at 5.5 months. Physiologically, syntaxin-6 knockout exerted a protective effect on weight trajectories and measures of frailty. Reduced neurodegeneration in the superficial cortex was observed at 3 months, as well as higher synaptic coverage at 5 months of age, supporting preserved neuropathological measures related to function. We further observed localised increases in tau pathology in the spinal cord and defined brain regions in young Stx6-/-;hTauP301S/P301S mice, despite total tau levels being comparable, in keeping with altered trafficking of pathological tau species with syntaxin-6 knockout. Despite a partial, early phenotypic rescue of functional measures, terminal endpoint comparisons were confounded by a 20% weight loss culling rule, as knockout mice maintained higher absolute weight. Taken together, this study functionally validates a role for syntaxin-6 in tauopathy pathogenesis, with syntaxin-6 knockout resulting in an early protective effect on multiple disease-relevant phenotypes in a humanised tauopathy model.
2026-03-17 | Natural Killer Subset Changes and Vascular Endothelial Growth Factor-A Plasma Profile in Progressive Supranuclear Palsy: The NKscape Study.
Emerging evidence implicates neuroinflammation in progressive supranuclear palsy (PSP) pathophysiology, with elevated cyto-chemokines suggesting natural killer (NK) cell involvement. We characterized peripheral NK in PSP (N = 11) versus Parkinson's disease (PD, N = 10) and healthy controls (HC, N = 8) at both immunophenotypic and transcriptional levels. PSP patients showed significantly reduced CD3-CD56 + NK frequency (1.35% ± 0.98%) compared with HC (2.96% ± 1.14%) and PD (2.03% ± 0.86%), specifically affecting the immunoregulatory CD56brightCD16-/dim subset. PSP NK cells exhibited elevated CX3CR1 expression, suggesting enhanced migratory capacity toward inflamed tissues. Transcriptomic analysis of primary NK cells revealed 208 DEG with significant enrichment in angiogenesis pathways, particularly vascular endothelial growth factor-A (VEGF-A). Plasma VEGF-A measurements demonstrated a disease-specific pattern: inverse correlation with severity in PSP versus direct correlation in PD. These findings identify a potentially disease-specific transcriptional signature with repercussions on the cyto-chemokine plasma profile. Further investigation of the NK cell-mediated immune response in PSP may provide new insights into disease mechanisms and open avenues for immunomodulatory therapeutic strategies. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2025-06-13 | The potential of proteomics for in-depth molecular investigations of progressive supranuclear palsy.
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder. The lack of comprehension about the pathogenesis of the disease, its heterogeneity, and the complex clinical evaluation in early stages, limit the development of effective treatments for PSP patients and highlight the need of further research on the field. In this work, we review the current knowledge of the physio- and neuropathology of PSP, its clinical features, diagnosis markers, and treatment options. We also compare the proteomic-based studies done to date in brain tissues as well as in cerebrospinal fluid and other non-cerebral samples, briefly describing the proteomic approach used and the biological findings obtained in each study. PSP is a complex neurodegenerative disorder marked by tau aggregation, glial dysfunction, and neuroinflammation. Although advances in neuroimaging and biofluid biomarkers have improved PSP diagnostic accuracy, no disease-modifying therapies are currently available. Promising avenues such as tau PET tracers, seed amplification assays, and advanced proteomic-based approaches are enhancing our ability to detect disease-specific tau pathology and hold the potential to provide novel biomarkers for earlier and more precise clinical diagnosis and treatment development that could transform the landscape of PSP.
2025-01-30 | Sensitive detection and propagation of brain-derived tau assemblies in HEK293-based wild-type tau seeding assays.
The assembly of tau into filaments defines tauopathies, a group of neurodegenerative diseases including Alzheimer's disease (AD), Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). The seeded aggregation of tau has been modeled in cell culture using pro-aggregate modifications such as truncation of N- and C-termini and point mutations within the microtubule-binding repeat domain. This limits the applicability of research findings to sporadic disease, where aggregates contain wild-type, full-length tau. We describe a sensitive and specific biosensor assays for brain-derived tau species utilizing wild-type 0N3R and 0N4R tau expressed in HEK293 cells. We further generate a cell line that propagates AD-templated insoluble tau which is hyperphosphorylated at disease-relevant sites and retains a seeding profile similar to AD. We propose these systems as an advance over existing cell-based seeding assays, as they display specificity to the conformation and isoform composition of sporadic human disease.
2025-01-20 | Idiopathic normal pressure hydrocephalus concomitant with progressive supranuclear palsy.
Recent studies by us and others have unveiled a frequent coexistence of idiopathic normal pressure hydrocephalus (iNPH) with neurodegenerative movement disorders, including progressive supranuclear palsy (PSP). This study aims to explore the clinical and radiological characteristics of patients with iNPH who also had comorbid with PSP, referred to as iNPHc + PSP. We retrospectively analyzed patients with iNPH admitted to our department between 2009 and 2024. We adhered to the established clinical criteria for iNPH and the Movement Disorder Society (MDS)-PSP criteria for probable or possible PSP with minor modifications. Among 85 iNPH patients, 18 were categorized as having iNPHc + PSP (21.2 %). Clinically, comorbid PSP led to impaired vertical eye movement, axial-dominant parkinsonism, and a propensity to fall backward in iNPH (p = 0.022, p = 0.002, and p < 0.005, respectively). Radiologically, comorbid PSP demonstrated a shortened mesencephalic tegmentum length in the magnetic resonance imaging and an asymmetrical deficit of dopamine transporter activities in the DaTscan (p = 0.0005, p = 0.0129, respectively). Lumboperitoneal shunt (LPS) surgery improved the modified Rankin scale (p = 0.038) and the iNPH grading scale (total score, p = 0.003; gait disturbance, p = 0.020; urinary incontinence, p = 0.026) one-year after surgery. PSP can coexist with iNPH, and detailed clinical and radiological assessment can aid in detecting this comorbidity. Importantly, LPS surgery can improve outcomes of patients with iNPHc + PSP.
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Drug Discovery Landscape
32 orphan drug designations for Progressive supranuclear palsy.
32 orphan drug designations for Progressive supranuclear palsy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
rifampin | small molecules | FDA | — | Medilabo RFP, Inc. |
sodium selenate | small molecules | FDA | — | Monash University |
2'-methoxyethyl antisense gapmer oligonucleotide against MAPT mRNA | oligonucleotides | EMA | Novartis Europharm Limited | |
2'-methoxyethyl antisense gapmer oligonucleotide against MAPT mRNA | oligonucleotides | FDA | Novartis Pharmaceuticals Corporation | |
a fully human IgG1k anti-programmed death ligand-1 (PD-L1) monoclonal antibody | antibodies | FDA | — | ImmunoBrain Checkpoint Inc. |
Tertomotide | peptides | EMA | Pharmaceutical Research Associates Group B.V. | |
tertomotide | peptides | FDA | GemVax & KAEL Co., Ltd. | |
Sodium selenate | small molecules | EMA | — | Monash University |
izaflortaucipir (proposed INN) | small molecules | FDA | Lantheus Biosciences Ltd. | |
Fasudil | small molecules | FDA | Woolsey Pharmaceuticals, Inc. | |
(S)-N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide, hydrochloride salt | small molecules | EMA | Ferrer Internacional S.A. | |
2-(2-(18F)fluoropyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine | small molecules | EMA | Lantheus Germany GmbH | |
Humanized IgG4 S228P monoclonal antibody targeting the cis conformation of the phosphorylated Thr231-Pro232 motif in tau | antibodies | FDA | — | Pinteon Therapeutics Inc. |
di-deuterated linoleic acid | small molecules | FDA | Retrotope, Inc. | |
competitive and reversible small molecule inhibitor of the O-linked-B-N-acetylglucosaminidase enzyme | small molecules | FDA | Ferrer Internacional, S.A. | |
1-(fluoro-18F)-3-((2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol | small molecules | FDA | Aprinoia Therapeutics | |
recombinant humanized IgG4P monoclonal antibody with specificity for human tau | antibodies | FDA | UCB, Inc. | |
N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine disulphate salt | small molecules | FDA | Alzprotect sas | |
tolfenamic acid | small molecules | FDA | Nasser H. Zawia | |
Tilavonemab | antibodies | EMA | Abbvie Deutschland GmbH & Co. KG | |
competetive small molecule inhibitor of the enzyme O-GlcNAcase | small molecules | FDA | — | Merck & Company, Inc. |
Tolfenamic acid | small molecules | EMA | RV Developpement | |
Humanised IgG4 monoclonal antibody against extracellular tau | antibodies | EMA | Biogen Netherlands B.V. | |
Anti-eTau Humanized IgG4 Monoclonal Antibody | antibodies | FDA | Biogen, Inc. | |
N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine disulphate salt | small molecules | EMA | AlzProtect sas | |
recombinant humanized anti-tau antibody | antibodies | FDA | AbbVie, Inc. | |
(2'R,3'S)-2'-hydroxy-N-carboxy-3'-amino-5'-methyl-hexanoic,N-tert-butyl ester, 13 ester 5B-20-epoxy-1B,2a,4a,7B,9a,10a,13a-heptahydroxy-4,10-diacetate-2-benzoate-(1"S)-7,9-acrolein acetal-11(15-1)-abeotaxane | small molecules | FDA | CNS Pharmaceuticals, Inc. | |
5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride | small molecules | FDA | — | Mithridion, Inc. |
Methylthioninium | small molecules | EMA | — | Pharma Gateway AB |
davunetide | peptides | FDA | Allon Therapeutics, Inc. | |
Tideglusib | — | EMA | — | [INACTIVE] Noscira S.A. |
4-benzyl-2-(a-naphtyl)-1,2,4-thiadiazolidine-3,5-dione | small molecules | FDA | — | NOSCIRA, S.A. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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