RARE DISEASE
Corticobasal syndrome
Corticobasal syndrome
Corticobasal syndrome
Drug discovery
1
drug
With orphan designation
Overview
Corticobasal syndrome (CBS) is a rare, progressive neurodegenerative disorder characterized by asymmetric parkinsonism, apraxia, dystonia, cortical sensory loss, and cognitive-behavioral deficits. It arises from diverse pathologies, including corticobasal degeneration, Alzheimer’s disease, and tauopathies. Diagnosis relies on clinical evaluation and neuroimaging showing asymmetric frontoparietal atrophy. Symptoms progress to severe disability, with survival averaging 6–8 years [9][14][19].
Key Clinical Insights
Burden
Rapid progression: Median survival 7 years, with motor disability, falls, dysphagia, and aspiration pneumonia as major morbidities [9][19].
Caregiver strain: High due to functional dependence and behavioral changes [10][13].
Economic impact: Requires multidisciplinary care, rehabilitation, and palliative services [3][18].
Early multidisciplinary intervention and realistic treatment goals are critical to optimizing quality of life.
Therapies
Motor symptoms: Levodopa (limited efficacy) [1][3], botulinum toxin for dystonia [8][18], clonazepam/levetiracetam for myoclonus [1][8].
Cognitive/behavioral: SSRIs for depression [1][3], atypical antipsychotics for agitation (use cautiously) [1][3].
Non-pharmacologic: Physical, occupational, and speech therapy to manage functional decline [3][6][18].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
185 drug discovery papers about Corticobasal syndrome, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
185 drug discovery papers about Corticobasal syndrome, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-16 | Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?
Many neurodegenerative diseases are characterized by pathological protein aggregation in the brain. Alzheimer's disease displays amyloid-β and tau inclusions in the form of amyloid-β plaques and tau neurofibrillary tangles. Synucleinopathies comprise Parkinson's disease and Dementia with Lewy bodies, which are classified by α-synuclein depositions in the form of Lewy bodies, as well as multiple system atrophy, which displays glial cytoplasmic α-synuclein inclusions. Tar DNA binding protein 43 (TDP-43) inclusions are observed in amyotrophic lateral sclerosis and frontotemporal lobar dementia with TDP-43 inclusions. A separate subgroup of frontotemporal lobar dementias, including Pick's disease, progressive supranuclear palsy and corticobasal degeneration, are characterized by disease-specific patterns of tau pathology and are termed primary tauopathies. Despite these classifications, it is not often appreciated that neurodegenerative diseases commonly display amyloid-β, tau, α-synuclein, and/or TDP-43 co-pathologies not typically associated with that specific disease's pathophysiology. Additionally, in vitro and in vivo proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.
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.
2026-07-02 | In-depth multimodal validation of 18F-THK5351 for imaging monoamine oxidase-B-mediated reactive astrogliosis in Alzheimer's and related neurodegenerative diseases.
18F-THK5351, initially developed as a positron-emission tomography (PET) tracer for tau pathology, was later shown to display high affinity for monoamine oxidase-B (MAO-B), raising uncertainty about the biological origin of its brain signals in neurodegenerative diseases. To resolve this ambiguity, we implemented a multi-scale validation framework integrating enzyme activity inhibition assays, molecular docking, biolayer interferometry, autoradiography, multiple transgenic and viral animal models, and human PET imaging. THK5351 selectively inhibited MAO-B while sparing MAO-A and exhibited reversible binding kinetics to recombinant MAO-B. Computational modelling localized THK5351 near the MAO-B substrate funnel, revealing moderate binding energy and weaker π-π stacking interactions compared with selective tau tracers. Autoradiographic analysis of human cortical tissue demonstrated that tracer binding was dominated by MAO-B-related signals, with a smaller contribution from tau aggregates, a difference insufficient to produce visually distinguishable patterns in clinical imaging. In APP/PS1 mice, 18F-THK5351 uptake colocalized with regions of reactive astrogliosis and was abolished by MAO-B inhibition, whereas overexpression of P301L-hTau induced extensive tau deposition without affecting tracer retention. MAO-B knockout reduced both tracer binding and tau phosphorylation, and viral induction of astrogliosis elevated tracer uptake that was reversed by selective MAO-B blockade. In a patient with corticobasal syndrome, tracer signals decreased during selegiline treatment and reappeared after drug withdrawal, mirroring preclinical pharmacological responses. Collectively, these findings demonstrate that 18F-THK5351 uptake primarily reflects MAO-B-mediated reactive astrogliosis rather than tau pathology, providing mechanistic insight into its signal origin and underscoring the value of cross-scale, multimodal validation in PET tracer development for neurodegenerative disease research.
2026-05-27 | Rhizomes as Multi-Target Pharmacological Platforms Against Tauopathy: Neuro-Metabolic Crosstalk, Drug-Likeness, and Translational Challenges.
Tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse "multi-target platforms" whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from "single-compound optimism" to network pharmacology with translational discipline.
2026-04-01 | Amyloid PET-guided anti-amyloid therapy in corticobasal syndrome associated with clinical improvement.
Corticobasal syndrome (CBS), a heterogeneous clinical phenotype, can be associated with various underlying pathologies. Although neuropathological studies show that CBS cases can be attributed to Alzheimer's disease (AD), in vivo confirmation and subsequent disease-modifying therapy remain rarely reported. In our patients presenting with clinical features consistent with CBS, amyloid positron emission tomography (PET) facilitated the diagnosis of underlying AD pathology and enabled the initiation of anti-amyloid therapy. We retrospectively reviewed patients with probable corticobasal degeneration from two tertiary centers who underwent amyloid PET confirming AD, systematically collecting clinical, imaging, and treatment data. Two patients were identified who fulfilled the inclusion criteria. In both patients, episodic memory was impaired, which was inconsistent with a typical corticobasal syndrome phenotype. Amyloid PET demonstrated widespread cortical and subcortical amyloid deposition, confirming underlying AD pathology. Based on these findings, anti-amyloid therapy was initiated, and clinical improvement was observed in both patients, although causality cannot be inferred from this uncontrolled retrospective observation. Corticobasal syndrome may be an atypical clinical presentation of AD pathology. Importantly, molecular imaging allowed an in vivo diagnosis of AD and facilitated the timely initiation of anti-amyloid therapy. This novel report documents the clinical implementation of amyloid PET guided anti-amyloid therapy in patients presenting with CBS.
proteins
2024-08-27 | FibrilPaint targets amyloid fibrils for ubiquitination
Abstract Neurodegenerative diseases are characterised by the progressive loss of neuronal tissue, and the accumulation of amyloid fibrils. Currently, there are no therapeutics that remove these amyloids. Targeted protein degradation could be a promising strategy to remove fibrils or oligomeric precursors. This approach requires degraders that specifically recognise amyloid fibrils, preferentially in early stages. Here, we introduce FibrilPaint20 (FP20), a peptide that specifically mediates the ubiquitination of amyloid fibrils. It acts as a PROTAC, containing both of a fibril recognition module and a recruitment motif for the E3 ubiquitin ligase CHIP. Importantly, FP20 does not bind to the functional monomer but exclusively to fibrils. Remarkably, FP20 ubiquitinates a set chemically diverse fibrils, unrelated in sequence and morphology. This includes fibrils of the disease-related proteins of α-synuclein, Aβ, Huntingtin and various Tau species, such as patient-derived fibrils from Alzheimer, Frontotemporal Dementia and Corticobasal Degeneration. This makes FP20 interesting for targeting mixed pathologies. Together, FP20 is an attractive lead compound for targeted protein degradation of amyloid fibrils.
2024-07-18 | Sensitive detection and propagation of brain-derived tau assemblies in HEK293 based wild-type tau seeding assays
Abstract The assembly of tau into filaments defines the 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 modelled in cell culture using pro-aggregant modifications such as truncation of the N- and C-termini and point-mutations within the tau microtubule-binding repeat domain. While providing experimental convenience, this limits the applicability of research findings to sporadic disease, where filaments contain wild-type, full-length tau isoforms. We therefore aimed to develop a sensitive and specific biosensor assay for the seeded aggregation of brain-derived tau species utilizing full-length, wild-type tau stably expressed in HEK293 cells. We show that addition of brain-derived tau extracted from cases of AD, PiD, CBD, or PSP induces the formation of HA- or GFP-tagged 0N3R or 0N4R tau aggregates. By isolating and expanding a single cell containing AD-seeded aggregates, we generated a cell line that propagates insoluble tau. We demonstrate that HEK293-propagated tau is hyperphosphorylated at disease relevant sites and retains a seeding profile similar to AD brain-derived material. We propose that these cell lines will aid pre-clinical, high-throughput screening for modifiers of seeded aggregation with greater conformational and strain specificity than existing cell-based biosensor assays.
2023-11-28 | Tau P301L mutation promotes core 4R tauopathy fibril fold through near-surface water structuring and conformational rearrangement
Abstract Tau forms toxic fibrillar aggregates in a family of neurodegenerative diseases known as tauopathies. The faithful replication of tauopathy-specific fibril structures is a critical gap for developing diagnostic and therapeutic tools. This study debuts a strategy of identifying a critical segment of tau that forms a folding motif that is characteristic of a family of tauopathies and isolating it as a standalone peptide that form seeding-competent fibrils. The 19-residue jR2R3 peptide (295-313) spanning the R2/R3 splice junction of tau, in the presence of P301L, forms seeding-competent amyloid fibrils. This tau fragment contains the hydrophobic VQIVYK hexapeptide that is part of the core of every pathological tau fibril structure solved to-date and an intramolecular counter-strand that stabilizes the strand-loop-strand (SLS) motif observed in 4R tauopathy fibrils. This study shows that P301L exhibits a duality of effects: it lowers the barrier for the peptide to adopt aggregation-prone conformations and enhances the local structuring of water around the mutation site that facilitates site-specific dewetting and in-register stacking of tau to form cross β-sheets. We solve a 3 Å cryo-EM structure of jR2R3-P301L fibrils with a pseudo 2 1 screw symmetry in which each half of the fibril’s cross-section contains two jR2R3-P301L peptides. One chain adopts a SLS fold found in 4R tauopathies that is stabilized by a second chain wrapping around the SLS fold, reminiscent of the 3-fold and 4-fold structures observed in 4R tauopathies. These jR2R3-P301L fibrils are able to template full length tau in a prion-like fashion. Significance Statement This study presents a first step towards designing a tauopathy specific aggregation pathway by engineering a minimal tau prion building block, jR2R3, that can template and propagate distinct disease folds. We present the discovery that P301L—among the widest used mutations in cell and animal models of Alzheimer’s Disease—destabilizes an aggregation-prohibiting internal hairpin and enhances the local surface water structure that serves as an entropic hotspot to exert a hyper-localized effect in jR2R3. Our study suggests that P301L may be a more suitable mutation to include in modeling 4R tauopathies than for modelling Alzheimer’s Disease, and that mutations are powerful tools for the purpose of designing of tau prion models as therapeutic tools.
2023-07-28 | Passaging Human Tauopathy Patient Samples in Cells Generates Heterogeneous Fibrils with a Subpopulation Adopting Disease Folds.
The discovery by cryo-electron microscopy (cryo-EM) that the neu-ropathological hallmarks of different tauopathies, including Alzheimer's disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), are caused by unique misfolded conformations of the protein tau is among the most profound developments in neurodegenerative disease research. To capitalize on these discoveries for therapeutic development, one must achieve in vitro replication of tau fibrils that adopt the representative tauopathy disease folds, which represents a grand challenge for the field. A widely used approach has been seeded propagation using pathological tau fibrils derived from post-mortem patient samples in biosensor cells that expresses a fragment of the tau protein known as K18, or Tau4RD, containing the microtubule-binding repeat domain of tau as the substrate. The new insights from cryo-EM raised the question of whether the Tau4RD fragment is capable of adopting characteristic tau folds found in CBD and PSP patient fibrils, and whether cell-passaged and amplified tau fibrils can be used as seeds to achieve cell-free assembly of recombinant 4R tau into fibrils without the addition of cofactors. Using Double Electron Electron Resonance (DEER) spectroscopy, we discovered that cell-passaged pathological seeds generate heterogeneous fibrils that are, however, distinct between the CBD and PSP lysate-seeded fibrils, and vastly different from heparin-induced tau fibril structures. Moreover, the lysate-seeded fibrils contain a characteristic sub-population that resembles the disease fold corresponding to the respective starting patient sample. These findings indicate that templated propagation using CBD and PSP patient-derived fibrils is possible with a tau fragment that does not contain the entire pathological fibril core, but also that additional mechanisms must be tuned to converge on a homogeneous fibril population.
2020-06-30 | Dystonia in atypical parkinsonian disorders.
Dystonia is common in the classic atypical parkinsonian disorders such as multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, and to a lesser extent in dementia with Lewy bodies. Its clinical phenomenology, including body distribution, timing of appearance, severity, and relationship to dopaminergic and other medications may vary considerably within and between atypical parkinsonian disorders. From a pathophysiological standpoint, the coexistence of dystonia with parkinsonism challenges the functional model of the basal ganglia. Clinical recognition of specific dystonic features may assist in the differential diagnosis of atypical parkinsonian disorders and in distinguishing them from Parkinson's disease. The presence of dystonia in atypical parkinsonian disorders informs management decisions. Reduction or withdrawal of levodopa should be considered if there is a close relationship between the onset of dystonia with periods of high dopaminergic tone. Botulinum neurotoxin may be considered in focal presentations. We here provide an updated overview of dystonia arising in the setting of atypical parkinsonian disorders, summarizing relevant clinical and clinicopathological studies, underlying pathophysiological mechanisms, diagnostic clues and potential pitfalls in the diagnosis. Finally, we suggest a tailored therapeutic approach for the management of these patients.
gene therapies
2026-08-25 | Gene-Environment Interaction in Nonfamilial Corticobasal Syndrome in Monozygotic Twins With Differential Occupational Exposure
Corticobasal syndrome (CBS) is a progressive neurodegenerative disorder often linked to 4-repeat tauopathies. Most CBS cases are nonfamilial and lack identified pathogenic variants, raising the possibility of environmental contributors, polygenic risk factors, and gene-environment interactions.
2026-04-04 | Sex differences for clinical presentations and co-pathologies in four-repeat tauopathies.
Four-repeat (4R)-tauopathies cause variable clinical profiles leading to clinical misdiagnosis. While sex differences are reported in Alzheimer's disease (AD), Lewy body disease (LBD), and clinically-defined frontotemporal dementia (FTD), little is known in 4R-tauopathies. National Alzheimer's Coordinating Center data were used for pathologically-defined 4R-tauopathies: progressive supranuclear palsy (PSP, n = 175), corticobasal degeneration (CBD, n = 114), argyrophilic grain disease (AGD, n = 230), Other-4R (n = 67). Sex differences for clinical presentation and co-pathologies were assessed adjusting for age and multiple comparisons. Most common clinical diagnosis was PSP (41%) for PSP; unspecified FTD (36%) for CBD; AD for AGD (57%) and Other-4R groups (48%), without sex differences. Females had less cognitive decline, apathy, motor symptoms; were older at cognitive, behavioral change onset. Males were more likely to demonstrate LBD co-pathology and clinical profile. Both females and males have low clinical diagnostic accuracy for 4R-tauopathies. Females with 4R-tauopathies may experience less severe clinical presentations and less co-pathology.
2026-02-22 | CSF tau levels in PSP and CBS
Anonymized dataset containing demographics, clinical characteristics, and cerebrospinal fluid tau protein concentrations from patients with progressive supranuclear palsy and corticobasal syndrome evaluated by movement disorders neurologists at the University of Cincinnati from 2013 through August 2025. The dataset follows the standardized variable names and formatting used by the U.S. National Institutes of Health/National Institute of Neurological Disorders and Stroke Common Data Elements (https://www.commondataelements.ninds.nih.gov) and the Movement Disorder Society (https://movementdisorders.org).
2026-02-12 | Real-world evaluation of Armstrong's criteria in corticobasal degeneration: Phenotypic overlap and diagnostic challenges.
Corticobasal degeneration (CBD) is a four-repeat tauopathy with heterogeneous clinical manifestations. Armstrong's criteria involve a two-step diagnostic approach: first, classifying patients into five clinical phenotypes-probable/possible corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), non-fluent/agrammatic variant primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS); second, determining whether they meet the clinical research criteria for probable CBD (cr-CBD) or the clinical criteria for possible CBD (p-CBD), which are distinct from the initial CBS classifications. To investigate how real-world patients with suspected CBD fulfill Armstrong's clinical phenotypes and diagnostic criteria, and to compare clinical and imaging features between the Alzheimer's disease (AD) group and the non-AD group defined by CSF amyloid biomarkers. We retrospectively reviewed 137 patients undergoing differential diagnosis for CBS, frontotemporal dementia, primary progressive aphasia, or PSPS. Of these, 78 met the criteria for cr-CBD (n = 36) or p-CBD (n = 42). CSF was examined in 32 patients, and based on the CSF Aβ42/40 ratio, patients were classified into an AD-group (AD-CBS; n = 6) and a non-AD group (n = 26). Among patients classified as cr-CBD or p-CBD, 79% fulfilled two or more clinical phenotypes, with FBS and PSPS most commonly. Compared with the AD group, the non-AD group showed more parkinsonian features and frontal hypoperfusion on [123I]-IMP SPECT. Armstrong's criteria captured a spectrum of overlapping clinical features. While helpful in clinical phenotyping, further validation with biomarkers is essential to distinguish CBD from AD and related disorders. Prospective studies with pathological confirmation are warranted.
2026-01-01 | Incidence and survival rates of frontotemporal lobar degeneration : population-based registry study
Background and Objectives - Frontotemporal lobar degeneration (FTLD) can present as a behavioral or language variant (bvFTLD or a primary progressive aphasia [PPA], or as a syndrome with parkinsonism, such as corticobasal syndrome [CBS] or progressive supranuclear palsy [PSP]). The incidence of FTLD varies in epidemiologic studies, reaching 3 per 100,000 person-years. Only few data exist regarding survival times. We evaluated incidence and survival rates in a population-based registry with high coverage in Southern Germany. - Methods - The epidemiologic ALS-FTLD registry Swabia covers a population of 8.4 million inhabitants in south-west Germany. Raw and age-standardized incidence rates, as well as incidence rate ratios (IRR) with 95% CIs were calculated. Median survival time was estimated for different FTLD variants using the Kaplan-Meier method. - Results - Between 2015 and 2022, 515 patients with FTLD (mean age at diagnosis 68.0 ± 9.5 years, 59.8% men) were registered. The median diagnostic delay was 24.8 months. The most common variant was bvFTLD (n = 185, 35.9%; 66.5% men), followed by PPA (n = 147, 28.5%; 51.0% men), PSP (n = 133, 25.8%; 62.9% men), and CBS (n = 22, 4.3%; 50% men). The overall FTLD incidence was 0.77 (95% CI 0.71-0.84), and the age-standardized incidence was 0.76 (95% CI 0.69-0.82) per 100.000 person-years. The age-standardized incidence was higher in men than in women, with an IRR of 1.73 (95% CI 1.44-2.00). In men, incidence increased from the age 50 years, primarily due to bvFTD, whereas in women this rise was primarily due to PSP. The median survival (N = 392) from diagnosis was 53.6 months (95% CI 50.9-62.0) overall, 73.1 months (95% CI 63.6-82.8) for patients with PPA, 42.8 months (95% CI 35.1-64.3) for patients with bvFTD, and 49.5 months (95% CI 39.2-53.7) for patients with PPS/CBS. - Discussion - We observed a raw incidence rate of 0.77, thus considerably lower than in most previous reports. Incidence was substantially higher in men than in women. The prognosis from the time of diagnosis depended highly on the specific FTLD subtype. Our data are based on the large sample size and high capture rate of a central European population-based registry.
antibodies
2025-07-21 | A new nosology for neurodegenerative dementias: cognitive proteinopathies - Shifting from “Where” to “What”
Over the next 100 years, the neuropathology of each of these diseases was studied in greater detail. For instance, alpha-synuclein was identified in Parkinson's disease, beta-amyloid and phospho-tau in Alzheimer's disease, and tau and TDP-43 in Pick's disease. At the same time, typical and atypical forms of these pathologies began to be described. In frontotemporal disease, for instance, the classic behavioral variant and the rare aphasic variant have been described. Similarly, Alzheimer's disease has both classical (amnesic) and atypical variants including frontal, posterior cortical, aphasic and, more recently, Down's disease. Alpha-synuclein is the most important factor in Parkinson's disease, which is associated with Lewy bodies disease. However, in parkinsonian syndromes such as progressive supranuclear palsy or corticobasal degeneration, the change is a tauopathy. Therefore, these phenotypes, which only describe “where” the lesion is located cannot be maintained. For example, a patient presenting with a behavioral disturbance such as apathy and disinhibition may have tauopathy, or TDP-43-opathy, or even beta amyloidosis. Over the last 10 years, neuropathological, and genetic research, as well as the emergence of biomarkers, has enabled us to diagnose the syndrome and identify the protein change that causes it during life. This is insignificant in the context of the new diagnostic criteria, and the new treatments targeting abnormal proteins or altered pathways, such as anti-amyloid, anti-tau, anti-sortilin antibodies. In the coming years, we will therefore move from diagnosing “where” to diagnosing “what” disease produces these symptoms.
2025-05-27 | The Role of Tau in Neuronal Function and Neurodegeneration.
Tau protein plays a pivotal role in maintaining neuronal structure and function through its regulation of microtubule stability and neuronal polarity. Encoded by the MAPT gene, Tau exists in multiple isoforms due to alternative mRNA splicing, with differential expression in the central and peripheral nervous systems. In healthy neurons, tau mRNA is selectively localized and translated in axons, a process tightly regulated by untranslated regions (UTRs) and RNA-binding proteins such as HuD and FMRP. Pathologically, Tau undergoes hyperphosphorylation, misfolding, and aggregation, which contribute to neurodegeneration in a range of disorders collectively known as tauopathies. Alzheimer's disease (AD) is the most prevalent tauopathy, where abnormal Tau accumulation in the temporal and frontal lobes correlates with cognitive decline and behavioral symptoms. Other tauopathies, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Frontotemporal Dementia with Parkinsonism (FTDP-17), and Pick's disease, are distinguished by the predominance of specific Tau isoforms (3R or 4R), cellular distribution, and affected brain regions. Notably, astroglial tauopathies highlight the pathological role of Tau accumulation in glial cells, expanding the understanding of neurodegeneration beyond neurons. Despite advances in imaging biomarkers (e.g., Tau-PET) and molecular diagnostics, effective disease-modifying therapies for tauopathies remain elusive. Ongoing research targets Tau through immunotherapies, splicing modulators, kinase inhibitors, and antisense oligonucleotides, aiming to mitigate Tau pathology and its deleterious effects. Understanding the multifaceted roles of Tau in neuronal and glial contexts is critical for developing future therapeutic strategies against tauopathies.
2025-01-13 | Selective Targeting of Pathogenic Tau Seeds via a Novel VHH
Abstract In Alzheimer’s disease (AD) and related tauopathies, progressive pathology has been linked to prion mechanisms, whereby ordered tau assemblies, or “seeds,” form in one cell and transit to neighboring or connected cells where they serve as templates for their own replication. Despite intensive efforts to develop early diagnosis and effective treatment, none has emerged. This is due partly to the structural heterogeneity of tau seeds and limitations in selectively targeting their pathogenic conformations. Here we report the discovery of a camelid variable heavy domain of heavy chain (VHH) that preferentially binds tau seeds of AD, corticobasal degeneration (CBD), and PS19 tauopathy mouse brains. From a published synthetic VHH yeast display library, we identified VHH clones that bound 2N4R tau monomer. After counter-screening for immunoprecipitation of seeding from human brain, we identified two seed-selective anti-tau VHH—VHH(510) and VHH(50)—that preferentially bound pathological tau. We enhanced the stability of these VHHs through framework mutations without affecting their seed-binding characteristics. We characterized VHH(510) in detail, determining that it binds the carboxy terminus of tau, maintains robust seed avidity even in the presence of competing monomer, and stains pathological tau inclusions in mouse and human AD tissues. These results highlight the power of seed-selective VHH to bind pathogenic tau, paving the way for future therapeutic and diagnostic applications across a wide range of neurodegenerative disorders.
2024-09-22 | A case of corticobasal syndrome possibly associated with anti-Yo antibodies.
Corticobasal syndrome (CBS) is a rare form of atypical parkinsonism, most commonly caused by neurodegenerative disorders. Autoimmune underlying conditions are extremely rare, and anti-Yo antibody-associated CBS has not been reported yet. Herein, we describe a case of a 68-year-old woman presenting with progressive dysarthria, gait instability and difficulty using her left hand with subacute deterioration during the last 3 months. Neurological examination revealed asymmetrical parkinsonism and pyramidal syndrome, reflex myoclonus and dystonia of her left upper limb, accompanied by apraxia of her left lower limb, fulfilling the criteria for possible CBS. Neuroimaging showed asymmetric frontoparietal atrophy, while cerebrospinal fluid and dopamine transporter imaging were normal. Prior to our evaluation, antineuronal autoantibody testing indicated positive anti-Yo antibodies. There was mild improvement after second IVIG cycle, and further investigation revealed no tumor. Although autoimmune etiology of this case cannot be certain, it highlights the potential expansion of the clinical spectrum of anti-Yo-associated paraneoplastic syndrome.
2024-05-03 | Anti-alpha synuclein and anti-tau immunotherapies: Can a cocktail approach work?
The hypothesis that neurodegenerative diseases are proteinopathies due to toxic effect of different underlying proteins, such as amyloid-beta and 3+4R-tau in Alzheimer's disease (AD) and alpha-synuclein in Parkinson's disease (PD), while still controversial is supported by several studies in the literature. This has led to conduct clinical trials attempting to reduce the load of these allegedly toxic proteins by immunotherapy, mostly but not solely based on antibodies against these proteins. Already completed clinical trials have ranged from initially negative results to recently partial positive outcomes, specifically for anti-amyloid antibodies in AD but also albeit to lesser degree for anti-synuclein antibodies in PD. Currently, there are several ongoing clinical trials in degenerative parkinsonisms with anti-synuclein approaches in PD and multiple system atrophy (MSA), as well as with anti-tau antibodies in 4R-tauopathies such as progressive supranuclear palsy (PSP). While it can be argued that expectations that part of these clinical trials will be positive can be hope or hype, it is reasonable to consider the future possibility of "cocktail" combination of different antibodies after the available experimental evidence of cross-talk between these proteins and neuropathological evidence of coexistence of these proteinopathies more frequently than expected by chance. Moreover, such "cocktail" approaches are widespread and accepted common practice in other fields such as oncology, and the complexity of neurodegenerative parkinsonisms makes reasonable the option for testing and eventually applying such combined approaches, should these prove useful separately, in the setting of patients with evidence of underlying concomitant proteinopathies, for example through biomarkers.
other
2025-04-10 | Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes.
Tau, a microtubule-binding protein linked to tauopathies like Alzheimer's disease and frontotemporal lobar degeneration (FTLD), has 3-repeat (3R) and 4-repeat (4R) isoforms. Accumulation of the 4R-tau is associated with FTLD, progressive supranuclear palsy (PSP), and cortico-basal degeneration (CBD). We previously showed that a loss of fused in sarcoma (FUS) or splicing factor, proline- and glutamine-rich (SFPQ) promoted 4R-tau accumulation, which induced FTLD-like behaviors and neurodegeneration in mice. Here, we developed antisense oligonucleotides (ASOs) modified with 2'-O, 4'-C-ethylene-bridged nucleic acids (ENAs), reducing the 4R-tau/3R-tau ratio while maintaining total tau expression from the MAPT gene. In vitro screening identified EN-06 as the most effective ENA. Intracerebroventricular (ICV) administration of EN-06 corrected the 4R/3R-tau ratio in FUS-silenced humanized tau mice and human iPSC-derived neurons. This treatment ameliorated disease phenotypes, including aberrant behaviors, spine dysmorphology, and neurodegeneration. The half-life of EN-06 after a single ICV administration was approximately 6 months in the brain, with splicing correction effects that persisted for 2 years. The efficacy of EN-06 was higher than that of 2'-O-methoxyethyl (MOE)-modified ASO (MO-06). These findings highlight the potential of ENA-modified ASOs to reduce 4R-tau while preserving total MAPT expression, thus offering a safe and long-acting treatment for 4R-tau-associated tauopathies.
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.
2023-06-15 | Focusing on oligomeric tau as a therapeutic target in Alzheimer's disease and other tauopathies.
Tau has commanded much attention as a potential therapeutic target in neurodegenerative diseases. Tau pathology is a hallmark of primary tauopathies, such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and subtypes of frontotemporal dementia (FTD), as well as secondary tauopathies, such as Alzheimer's disease (AD). The development of tau therapeutics must reconcile with the structural complexity of the tau proteome, as well as an incomplete understanding of the role of tau in both physiology and disease. This review offers a current perspective on tau biology, discusses key barriers to the development of effective tau-based therapeutics, and promotes the idea that pathogenic (as opposed to merely pathological) tau should be at the center of drug development efforts. An efficacious tau therapeutic will exhibit several primary features: 1) selectivity for pathogenic tau versus other tau species; 2) blood-brain barrier and cell membrane permeability, enabling access to intracellular tau in disease-relevant brain regions; and 3) minimal toxicity. Oligomeric tau is proposed as a major pathogenic form of tau and a compelling drug target in tauopathies.
2020-06-29 | A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.
Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.
2019-07-20 | C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy
Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.
small molecules
2026-09-16 | Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?
Many neurodegenerative diseases are characterized by pathological protein aggregation in the brain. Alzheimer's disease displays amyloid-β and tau inclusions in the form of amyloid-β plaques and tau neurofibrillary tangles. Synucleinopathies comprise Parkinson's disease and Dementia with Lewy bodies, which are classified by α-synuclein depositions in the form of Lewy bodies, as well as multiple system atrophy, which displays glial cytoplasmic α-synuclein inclusions. Tar DNA binding protein 43 (TDP-43) inclusions are observed in amyotrophic lateral sclerosis and frontotemporal lobar dementia with TDP-43 inclusions. A separate subgroup of frontotemporal lobar dementias, including Pick's disease, progressive supranuclear palsy and corticobasal degeneration, are characterized by disease-specific patterns of tau pathology and are termed primary tauopathies. Despite these classifications, it is not often appreciated that neurodegenerative diseases commonly display amyloid-β, tau, α-synuclein, and/or TDP-43 co-pathologies not typically associated with that specific disease's pathophysiology. Additionally, in vitro and in vivo proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.
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.
2026-07-02 | In-depth multimodal validation of 18F-THK5351 for imaging monoamine oxidase-B-mediated reactive astrogliosis in Alzheimer's and related neurodegenerative diseases.
18F-THK5351, initially developed as a positron-emission tomography (PET) tracer for tau pathology, was later shown to display high affinity for monoamine oxidase-B (MAO-B), raising uncertainty about the biological origin of its brain signals in neurodegenerative diseases. To resolve this ambiguity, we implemented a multi-scale validation framework integrating enzyme activity inhibition assays, molecular docking, biolayer interferometry, autoradiography, multiple transgenic and viral animal models, and human PET imaging. THK5351 selectively inhibited MAO-B while sparing MAO-A and exhibited reversible binding kinetics to recombinant MAO-B. Computational modelling localized THK5351 near the MAO-B substrate funnel, revealing moderate binding energy and weaker π-π stacking interactions compared with selective tau tracers. Autoradiographic analysis of human cortical tissue demonstrated that tracer binding was dominated by MAO-B-related signals, with a smaller contribution from tau aggregates, a difference insufficient to produce visually distinguishable patterns in clinical imaging. In APP/PS1 mice, 18F-THK5351 uptake colocalized with regions of reactive astrogliosis and was abolished by MAO-B inhibition, whereas overexpression of P301L-hTau induced extensive tau deposition without affecting tracer retention. MAO-B knockout reduced both tracer binding and tau phosphorylation, and viral induction of astrogliosis elevated tracer uptake that was reversed by selective MAO-B blockade. In a patient with corticobasal syndrome, tracer signals decreased during selegiline treatment and reappeared after drug withdrawal, mirroring preclinical pharmacological responses. Collectively, these findings demonstrate that 18F-THK5351 uptake primarily reflects MAO-B-mediated reactive astrogliosis rather than tau pathology, providing mechanistic insight into its signal origin and underscoring the value of cross-scale, multimodal validation in PET tracer development for neurodegenerative disease research.
2026-05-27 | Rhizomes as Multi-Target Pharmacological Platforms Against Tauopathy: Neuro-Metabolic Crosstalk, Drug-Likeness, and Translational Challenges.
Tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse "multi-target platforms" whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from "single-compound optimism" to network pharmacology with translational discipline.
2026-04-01 | Amyloid PET-guided anti-amyloid therapy in corticobasal syndrome associated with clinical improvement.
Corticobasal syndrome (CBS), a heterogeneous clinical phenotype, can be associated with various underlying pathologies. Although neuropathological studies show that CBS cases can be attributed to Alzheimer's disease (AD), in vivo confirmation and subsequent disease-modifying therapy remain rarely reported. In our patients presenting with clinical features consistent with CBS, amyloid positron emission tomography (PET) facilitated the diagnosis of underlying AD pathology and enabled the initiation of anti-amyloid therapy. We retrospectively reviewed patients with probable corticobasal degeneration from two tertiary centers who underwent amyloid PET confirming AD, systematically collecting clinical, imaging, and treatment data. Two patients were identified who fulfilled the inclusion criteria. In both patients, episodic memory was impaired, which was inconsistent with a typical corticobasal syndrome phenotype. Amyloid PET demonstrated widespread cortical and subcortical amyloid deposition, confirming underlying AD pathology. Based on these findings, anti-amyloid therapy was initiated, and clinical improvement was observed in both patients, although causality cannot be inferred from this uncontrolled retrospective observation. Corticobasal syndrome may be an atypical clinical presentation of AD pathology. Importantly, molecular imaging allowed an in vivo diagnosis of AD and facilitated the timely initiation of anti-amyloid therapy. This novel report documents the clinical implementation of amyloid PET guided anti-amyloid therapy in patients presenting with CBS.
proteins
2024-08-27 | FibrilPaint targets amyloid fibrils for ubiquitination
Abstract Neurodegenerative diseases are characterised by the progressive loss of neuronal tissue, and the accumulation of amyloid fibrils. Currently, there are no therapeutics that remove these amyloids. Targeted protein degradation could be a promising strategy to remove fibrils or oligomeric precursors. This approach requires degraders that specifically recognise amyloid fibrils, preferentially in early stages. Here, we introduce FibrilPaint20 (FP20), a peptide that specifically mediates the ubiquitination of amyloid fibrils. It acts as a PROTAC, containing both of a fibril recognition module and a recruitment motif for the E3 ubiquitin ligase CHIP. Importantly, FP20 does not bind to the functional monomer but exclusively to fibrils. Remarkably, FP20 ubiquitinates a set chemically diverse fibrils, unrelated in sequence and morphology. This includes fibrils of the disease-related proteins of α-synuclein, Aβ, Huntingtin and various Tau species, such as patient-derived fibrils from Alzheimer, Frontotemporal Dementia and Corticobasal Degeneration. This makes FP20 interesting for targeting mixed pathologies. Together, FP20 is an attractive lead compound for targeted protein degradation of amyloid fibrils.
2024-07-18 | Sensitive detection and propagation of brain-derived tau assemblies in HEK293 based wild-type tau seeding assays
Abstract The assembly of tau into filaments defines the 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 modelled in cell culture using pro-aggregant modifications such as truncation of the N- and C-termini and point-mutations within the tau microtubule-binding repeat domain. While providing experimental convenience, this limits the applicability of research findings to sporadic disease, where filaments contain wild-type, full-length tau isoforms. We therefore aimed to develop a sensitive and specific biosensor assay for the seeded aggregation of brain-derived tau species utilizing full-length, wild-type tau stably expressed in HEK293 cells. We show that addition of brain-derived tau extracted from cases of AD, PiD, CBD, or PSP induces the formation of HA- or GFP-tagged 0N3R or 0N4R tau aggregates. By isolating and expanding a single cell containing AD-seeded aggregates, we generated a cell line that propagates insoluble tau. We demonstrate that HEK293-propagated tau is hyperphosphorylated at disease relevant sites and retains a seeding profile similar to AD brain-derived material. We propose that these cell lines will aid pre-clinical, high-throughput screening for modifiers of seeded aggregation with greater conformational and strain specificity than existing cell-based biosensor assays.
2023-11-28 | Tau P301L mutation promotes core 4R tauopathy fibril fold through near-surface water structuring and conformational rearrangement
Abstract Tau forms toxic fibrillar aggregates in a family of neurodegenerative diseases known as tauopathies. The faithful replication of tauopathy-specific fibril structures is a critical gap for developing diagnostic and therapeutic tools. This study debuts a strategy of identifying a critical segment of tau that forms a folding motif that is characteristic of a family of tauopathies and isolating it as a standalone peptide that form seeding-competent fibrils. The 19-residue jR2R3 peptide (295-313) spanning the R2/R3 splice junction of tau, in the presence of P301L, forms seeding-competent amyloid fibrils. This tau fragment contains the hydrophobic VQIVYK hexapeptide that is part of the core of every pathological tau fibril structure solved to-date and an intramolecular counter-strand that stabilizes the strand-loop-strand (SLS) motif observed in 4R tauopathy fibrils. This study shows that P301L exhibits a duality of effects: it lowers the barrier for the peptide to adopt aggregation-prone conformations and enhances the local structuring of water around the mutation site that facilitates site-specific dewetting and in-register stacking of tau to form cross β-sheets. We solve a 3 Å cryo-EM structure of jR2R3-P301L fibrils with a pseudo 2 1 screw symmetry in which each half of the fibril’s cross-section contains two jR2R3-P301L peptides. One chain adopts a SLS fold found in 4R tauopathies that is stabilized by a second chain wrapping around the SLS fold, reminiscent of the 3-fold and 4-fold structures observed in 4R tauopathies. These jR2R3-P301L fibrils are able to template full length tau in a prion-like fashion. Significance Statement This study presents a first step towards designing a tauopathy specific aggregation pathway by engineering a minimal tau prion building block, jR2R3, that can template and propagate distinct disease folds. We present the discovery that P301L—among the widest used mutations in cell and animal models of Alzheimer’s Disease—destabilizes an aggregation-prohibiting internal hairpin and enhances the local surface water structure that serves as an entropic hotspot to exert a hyper-localized effect in jR2R3. Our study suggests that P301L may be a more suitable mutation to include in modeling 4R tauopathies than for modelling Alzheimer’s Disease, and that mutations are powerful tools for the purpose of designing of tau prion models as therapeutic tools.
2023-07-28 | Passaging Human Tauopathy Patient Samples in Cells Generates Heterogeneous Fibrils with a Subpopulation Adopting Disease Folds.
The discovery by cryo-electron microscopy (cryo-EM) that the neu-ropathological hallmarks of different tauopathies, including Alzheimer's disease, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), are caused by unique misfolded conformations of the protein tau is among the most profound developments in neurodegenerative disease research. To capitalize on these discoveries for therapeutic development, one must achieve in vitro replication of tau fibrils that adopt the representative tauopathy disease folds, which represents a grand challenge for the field. A widely used approach has been seeded propagation using pathological tau fibrils derived from post-mortem patient samples in biosensor cells that expresses a fragment of the tau protein known as K18, or Tau4RD, containing the microtubule-binding repeat domain of tau as the substrate. The new insights from cryo-EM raised the question of whether the Tau4RD fragment is capable of adopting characteristic tau folds found in CBD and PSP patient fibrils, and whether cell-passaged and amplified tau fibrils can be used as seeds to achieve cell-free assembly of recombinant 4R tau into fibrils without the addition of cofactors. Using Double Electron Electron Resonance (DEER) spectroscopy, we discovered that cell-passaged pathological seeds generate heterogeneous fibrils that are, however, distinct between the CBD and PSP lysate-seeded fibrils, and vastly different from heparin-induced tau fibril structures. Moreover, the lysate-seeded fibrils contain a characteristic sub-population that resembles the disease fold corresponding to the respective starting patient sample. These findings indicate that templated propagation using CBD and PSP patient-derived fibrils is possible with a tau fragment that does not contain the entire pathological fibril core, but also that additional mechanisms must be tuned to converge on a homogeneous fibril population.
2020-06-30 | Dystonia in atypical parkinsonian disorders.
Dystonia is common in the classic atypical parkinsonian disorders such as multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, and to a lesser extent in dementia with Lewy bodies. Its clinical phenomenology, including body distribution, timing of appearance, severity, and relationship to dopaminergic and other medications may vary considerably within and between atypical parkinsonian disorders. From a pathophysiological standpoint, the coexistence of dystonia with parkinsonism challenges the functional model of the basal ganglia. Clinical recognition of specific dystonic features may assist in the differential diagnosis of atypical parkinsonian disorders and in distinguishing them from Parkinson's disease. The presence of dystonia in atypical parkinsonian disorders informs management decisions. Reduction or withdrawal of levodopa should be considered if there is a close relationship between the onset of dystonia with periods of high dopaminergic tone. Botulinum neurotoxin may be considered in focal presentations. We here provide an updated overview of dystonia arising in the setting of atypical parkinsonian disorders, summarizing relevant clinical and clinicopathological studies, underlying pathophysiological mechanisms, diagnostic clues and potential pitfalls in the diagnosis. Finally, we suggest a tailored therapeutic approach for the management of these patients.
gene therapies
2026-08-25 | Gene-Environment Interaction in Nonfamilial Corticobasal Syndrome in Monozygotic Twins With Differential Occupational Exposure
Corticobasal syndrome (CBS) is a progressive neurodegenerative disorder often linked to 4-repeat tauopathies. Most CBS cases are nonfamilial and lack identified pathogenic variants, raising the possibility of environmental contributors, polygenic risk factors, and gene-environment interactions.
2026-04-04 | Sex differences for clinical presentations and co-pathologies in four-repeat tauopathies.
Four-repeat (4R)-tauopathies cause variable clinical profiles leading to clinical misdiagnosis. While sex differences are reported in Alzheimer's disease (AD), Lewy body disease (LBD), and clinically-defined frontotemporal dementia (FTD), little is known in 4R-tauopathies. National Alzheimer's Coordinating Center data were used for pathologically-defined 4R-tauopathies: progressive supranuclear palsy (PSP, n = 175), corticobasal degeneration (CBD, n = 114), argyrophilic grain disease (AGD, n = 230), Other-4R (n = 67). Sex differences for clinical presentation and co-pathologies were assessed adjusting for age and multiple comparisons. Most common clinical diagnosis was PSP (41%) for PSP; unspecified FTD (36%) for CBD; AD for AGD (57%) and Other-4R groups (48%), without sex differences. Females had less cognitive decline, apathy, motor symptoms; were older at cognitive, behavioral change onset. Males were more likely to demonstrate LBD co-pathology and clinical profile. Both females and males have low clinical diagnostic accuracy for 4R-tauopathies. Females with 4R-tauopathies may experience less severe clinical presentations and less co-pathology.
2026-02-22 | CSF tau levels in PSP and CBS
Anonymized dataset containing demographics, clinical characteristics, and cerebrospinal fluid tau protein concentrations from patients with progressive supranuclear palsy and corticobasal syndrome evaluated by movement disorders neurologists at the University of Cincinnati from 2013 through August 2025. The dataset follows the standardized variable names and formatting used by the U.S. National Institutes of Health/National Institute of Neurological Disorders and Stroke Common Data Elements (https://www.commondataelements.ninds.nih.gov) and the Movement Disorder Society (https://movementdisorders.org).
2026-02-12 | Real-world evaluation of Armstrong's criteria in corticobasal degeneration: Phenotypic overlap and diagnostic challenges.
Corticobasal degeneration (CBD) is a four-repeat tauopathy with heterogeneous clinical manifestations. Armstrong's criteria involve a two-step diagnostic approach: first, classifying patients into five clinical phenotypes-probable/possible corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), non-fluent/agrammatic variant primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS); second, determining whether they meet the clinical research criteria for probable CBD (cr-CBD) or the clinical criteria for possible CBD (p-CBD), which are distinct from the initial CBS classifications. To investigate how real-world patients with suspected CBD fulfill Armstrong's clinical phenotypes and diagnostic criteria, and to compare clinical and imaging features between the Alzheimer's disease (AD) group and the non-AD group defined by CSF amyloid biomarkers. We retrospectively reviewed 137 patients undergoing differential diagnosis for CBS, frontotemporal dementia, primary progressive aphasia, or PSPS. Of these, 78 met the criteria for cr-CBD (n = 36) or p-CBD (n = 42). CSF was examined in 32 patients, and based on the CSF Aβ42/40 ratio, patients were classified into an AD-group (AD-CBS; n = 6) and a non-AD group (n = 26). Among patients classified as cr-CBD or p-CBD, 79% fulfilled two or more clinical phenotypes, with FBS and PSPS most commonly. Compared with the AD group, the non-AD group showed more parkinsonian features and frontal hypoperfusion on [123I]-IMP SPECT. Armstrong's criteria captured a spectrum of overlapping clinical features. While helpful in clinical phenotyping, further validation with biomarkers is essential to distinguish CBD from AD and related disorders. Prospective studies with pathological confirmation are warranted.
2026-01-01 | Incidence and survival rates of frontotemporal lobar degeneration : population-based registry study
Background and Objectives - Frontotemporal lobar degeneration (FTLD) can present as a behavioral or language variant (bvFTLD or a primary progressive aphasia [PPA], or as a syndrome with parkinsonism, such as corticobasal syndrome [CBS] or progressive supranuclear palsy [PSP]). The incidence of FTLD varies in epidemiologic studies, reaching 3 per 100,000 person-years. Only few data exist regarding survival times. We evaluated incidence and survival rates in a population-based registry with high coverage in Southern Germany. - Methods - The epidemiologic ALS-FTLD registry Swabia covers a population of 8.4 million inhabitants in south-west Germany. Raw and age-standardized incidence rates, as well as incidence rate ratios (IRR) with 95% CIs were calculated. Median survival time was estimated for different FTLD variants using the Kaplan-Meier method. - Results - Between 2015 and 2022, 515 patients with FTLD (mean age at diagnosis 68.0 ± 9.5 years, 59.8% men) were registered. The median diagnostic delay was 24.8 months. The most common variant was bvFTLD (n = 185, 35.9%; 66.5% men), followed by PPA (n = 147, 28.5%; 51.0% men), PSP (n = 133, 25.8%; 62.9% men), and CBS (n = 22, 4.3%; 50% men). The overall FTLD incidence was 0.77 (95% CI 0.71-0.84), and the age-standardized incidence was 0.76 (95% CI 0.69-0.82) per 100.000 person-years. The age-standardized incidence was higher in men than in women, with an IRR of 1.73 (95% CI 1.44-2.00). In men, incidence increased from the age 50 years, primarily due to bvFTD, whereas in women this rise was primarily due to PSP. The median survival (N = 392) from diagnosis was 53.6 months (95% CI 50.9-62.0) overall, 73.1 months (95% CI 63.6-82.8) for patients with PPA, 42.8 months (95% CI 35.1-64.3) for patients with bvFTD, and 49.5 months (95% CI 39.2-53.7) for patients with PPS/CBS. - Discussion - We observed a raw incidence rate of 0.77, thus considerably lower than in most previous reports. Incidence was substantially higher in men than in women. The prognosis from the time of diagnosis depended highly on the specific FTLD subtype. Our data are based on the large sample size and high capture rate of a central European population-based registry.
antibodies
2025-07-21 | A new nosology for neurodegenerative dementias: cognitive proteinopathies - Shifting from “Where” to “What”
Over the next 100 years, the neuropathology of each of these diseases was studied in greater detail. For instance, alpha-synuclein was identified in Parkinson's disease, beta-amyloid and phospho-tau in Alzheimer's disease, and tau and TDP-43 in Pick's disease. At the same time, typical and atypical forms of these pathologies began to be described. In frontotemporal disease, for instance, the classic behavioral variant and the rare aphasic variant have been described. Similarly, Alzheimer's disease has both classical (amnesic) and atypical variants including frontal, posterior cortical, aphasic and, more recently, Down's disease. Alpha-synuclein is the most important factor in Parkinson's disease, which is associated with Lewy bodies disease. However, in parkinsonian syndromes such as progressive supranuclear palsy or corticobasal degeneration, the change is a tauopathy. Therefore, these phenotypes, which only describe “where” the lesion is located cannot be maintained. For example, a patient presenting with a behavioral disturbance such as apathy and disinhibition may have tauopathy, or TDP-43-opathy, or even beta amyloidosis. Over the last 10 years, neuropathological, and genetic research, as well as the emergence of biomarkers, has enabled us to diagnose the syndrome and identify the protein change that causes it during life. This is insignificant in the context of the new diagnostic criteria, and the new treatments targeting abnormal proteins or altered pathways, such as anti-amyloid, anti-tau, anti-sortilin antibodies. In the coming years, we will therefore move from diagnosing “where” to diagnosing “what” disease produces these symptoms.
2025-05-27 | The Role of Tau in Neuronal Function and Neurodegeneration.
Tau protein plays a pivotal role in maintaining neuronal structure and function through its regulation of microtubule stability and neuronal polarity. Encoded by the MAPT gene, Tau exists in multiple isoforms due to alternative mRNA splicing, with differential expression in the central and peripheral nervous systems. In healthy neurons, tau mRNA is selectively localized and translated in axons, a process tightly regulated by untranslated regions (UTRs) and RNA-binding proteins such as HuD and FMRP. Pathologically, Tau undergoes hyperphosphorylation, misfolding, and aggregation, which contribute to neurodegeneration in a range of disorders collectively known as tauopathies. Alzheimer's disease (AD) is the most prevalent tauopathy, where abnormal Tau accumulation in the temporal and frontal lobes correlates with cognitive decline and behavioral symptoms. Other tauopathies, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Frontotemporal Dementia with Parkinsonism (FTDP-17), and Pick's disease, are distinguished by the predominance of specific Tau isoforms (3R or 4R), cellular distribution, and affected brain regions. Notably, astroglial tauopathies highlight the pathological role of Tau accumulation in glial cells, expanding the understanding of neurodegeneration beyond neurons. Despite advances in imaging biomarkers (e.g., Tau-PET) and molecular diagnostics, effective disease-modifying therapies for tauopathies remain elusive. Ongoing research targets Tau through immunotherapies, splicing modulators, kinase inhibitors, and antisense oligonucleotides, aiming to mitigate Tau pathology and its deleterious effects. Understanding the multifaceted roles of Tau in neuronal and glial contexts is critical for developing future therapeutic strategies against tauopathies.
2025-01-13 | Selective Targeting of Pathogenic Tau Seeds via a Novel VHH
Abstract In Alzheimer’s disease (AD) and related tauopathies, progressive pathology has been linked to prion mechanisms, whereby ordered tau assemblies, or “seeds,” form in one cell and transit to neighboring or connected cells where they serve as templates for their own replication. Despite intensive efforts to develop early diagnosis and effective treatment, none has emerged. This is due partly to the structural heterogeneity of tau seeds and limitations in selectively targeting their pathogenic conformations. Here we report the discovery of a camelid variable heavy domain of heavy chain (VHH) that preferentially binds tau seeds of AD, corticobasal degeneration (CBD), and PS19 tauopathy mouse brains. From a published synthetic VHH yeast display library, we identified VHH clones that bound 2N4R tau monomer. After counter-screening for immunoprecipitation of seeding from human brain, we identified two seed-selective anti-tau VHH—VHH(510) and VHH(50)—that preferentially bound pathological tau. We enhanced the stability of these VHHs through framework mutations without affecting their seed-binding characteristics. We characterized VHH(510) in detail, determining that it binds the carboxy terminus of tau, maintains robust seed avidity even in the presence of competing monomer, and stains pathological tau inclusions in mouse and human AD tissues. These results highlight the power of seed-selective VHH to bind pathogenic tau, paving the way for future therapeutic and diagnostic applications across a wide range of neurodegenerative disorders.
2024-09-22 | A case of corticobasal syndrome possibly associated with anti-Yo antibodies.
Corticobasal syndrome (CBS) is a rare form of atypical parkinsonism, most commonly caused by neurodegenerative disorders. Autoimmune underlying conditions are extremely rare, and anti-Yo antibody-associated CBS has not been reported yet. Herein, we describe a case of a 68-year-old woman presenting with progressive dysarthria, gait instability and difficulty using her left hand with subacute deterioration during the last 3 months. Neurological examination revealed asymmetrical parkinsonism and pyramidal syndrome, reflex myoclonus and dystonia of her left upper limb, accompanied by apraxia of her left lower limb, fulfilling the criteria for possible CBS. Neuroimaging showed asymmetric frontoparietal atrophy, while cerebrospinal fluid and dopamine transporter imaging were normal. Prior to our evaluation, antineuronal autoantibody testing indicated positive anti-Yo antibodies. There was mild improvement after second IVIG cycle, and further investigation revealed no tumor. Although autoimmune etiology of this case cannot be certain, it highlights the potential expansion of the clinical spectrum of anti-Yo-associated paraneoplastic syndrome.
2024-05-03 | Anti-alpha synuclein and anti-tau immunotherapies: Can a cocktail approach work?
The hypothesis that neurodegenerative diseases are proteinopathies due to toxic effect of different underlying proteins, such as amyloid-beta and 3+4R-tau in Alzheimer's disease (AD) and alpha-synuclein in Parkinson's disease (PD), while still controversial is supported by several studies in the literature. This has led to conduct clinical trials attempting to reduce the load of these allegedly toxic proteins by immunotherapy, mostly but not solely based on antibodies against these proteins. Already completed clinical trials have ranged from initially negative results to recently partial positive outcomes, specifically for anti-amyloid antibodies in AD but also albeit to lesser degree for anti-synuclein antibodies in PD. Currently, there are several ongoing clinical trials in degenerative parkinsonisms with anti-synuclein approaches in PD and multiple system atrophy (MSA), as well as with anti-tau antibodies in 4R-tauopathies such as progressive supranuclear palsy (PSP). While it can be argued that expectations that part of these clinical trials will be positive can be hope or hype, it is reasonable to consider the future possibility of "cocktail" combination of different antibodies after the available experimental evidence of cross-talk between these proteins and neuropathological evidence of coexistence of these proteinopathies more frequently than expected by chance. Moreover, such "cocktail" approaches are widespread and accepted common practice in other fields such as oncology, and the complexity of neurodegenerative parkinsonisms makes reasonable the option for testing and eventually applying such combined approaches, should these prove useful separately, in the setting of patients with evidence of underlying concomitant proteinopathies, for example through biomarkers.
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2025-04-10 | Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes.
Tau, a microtubule-binding protein linked to tauopathies like Alzheimer's disease and frontotemporal lobar degeneration (FTLD), has 3-repeat (3R) and 4-repeat (4R) isoforms. Accumulation of the 4R-tau is associated with FTLD, progressive supranuclear palsy (PSP), and cortico-basal degeneration (CBD). We previously showed that a loss of fused in sarcoma (FUS) or splicing factor, proline- and glutamine-rich (SFPQ) promoted 4R-tau accumulation, which induced FTLD-like behaviors and neurodegeneration in mice. Here, we developed antisense oligonucleotides (ASOs) modified with 2'-O, 4'-C-ethylene-bridged nucleic acids (ENAs), reducing the 4R-tau/3R-tau ratio while maintaining total tau expression from the MAPT gene. In vitro screening identified EN-06 as the most effective ENA. Intracerebroventricular (ICV) administration of EN-06 corrected the 4R/3R-tau ratio in FUS-silenced humanized tau mice and human iPSC-derived neurons. This treatment ameliorated disease phenotypes, including aberrant behaviors, spine dysmorphology, and neurodegeneration. The half-life of EN-06 after a single ICV administration was approximately 6 months in the brain, with splicing correction effects that persisted for 2 years. The efficacy of EN-06 was higher than that of 2'-O-methoxyethyl (MOE)-modified ASO (MO-06). These findings highlight the potential of ENA-modified ASOs to reduce 4R-tau while preserving total MAPT expression, thus offering a safe and long-acting treatment for 4R-tau-associated tauopathies.
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.
2023-06-15 | Focusing on oligomeric tau as a therapeutic target in Alzheimer's disease and other tauopathies.
Tau has commanded much attention as a potential therapeutic target in neurodegenerative diseases. Tau pathology is a hallmark of primary tauopathies, such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and subtypes of frontotemporal dementia (FTD), as well as secondary tauopathies, such as Alzheimer's disease (AD). The development of tau therapeutics must reconcile with the structural complexity of the tau proteome, as well as an incomplete understanding of the role of tau in both physiology and disease. This review offers a current perspective on tau biology, discusses key barriers to the development of effective tau-based therapeutics, and promotes the idea that pathogenic (as opposed to merely pathological) tau should be at the center of drug development efforts. An efficacious tau therapeutic will exhibit several primary features: 1) selectivity for pathogenic tau versus other tau species; 2) blood-brain barrier and cell membrane permeability, enabling access to intracellular tau in disease-relevant brain regions; and 3) minimal toxicity. Oligomeric tau is proposed as a major pathogenic form of tau and a compelling drug target in tauopathies.
2020-06-29 | A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.
Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.
2019-07-20 | C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy
Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.
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Drug Discovery Landscape
1 orphan drug designation for Corticobasal syndrome.
1 orphan drug designation for Corticobasal syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Fasudil hydrochloride | small molecules | FDA | Woolsey Pharmaceuticals, Inc. |
“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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