RARE DISEASE
Multiple system atrophy
Multiple system atrophy
Multiple system atrophy
Synonyms: MSA, Multisystem atrophy
Synonyms: MSA, Multisystem atrophy
Synonyms: MSA, Multisystem atrophy
Drug discovery
18
drugs
With orphan designations
Overview
Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder characterized by autonomic dysfunction, parkinsonism, cerebellar ataxia, and corticospinal signs. It involves progressive α-synuclein aggregation in oligodendroglia, leading to neurodegeneration in striatonigral and olivopontocerebellar structures. Diagnosis requires clinical criteria (autonomic failure + parkinsonism/cerebellar features) and MRI findings (e.g., putaminal atrophy). Median survival is 6–10 years, with complications including dysphagia, infections, and sudden death [1][4][6][16].
Therapies
Symptomatic management: Levodopa (transient benefit in 20–30%), fludrocortisone/midodrine for orthostatic hypotension, urological interventions for incontinence [3][8][15].
Supportive care: Physiotherapy, speech therapy, and gastrostomy/PEG for dysphagia [11][15].
Emerging therapies: Monoclonal antibodies (e.g., amlenetug) targeting α-synuclein in Phase III trials [8].
Categories: rare neurological diseases
Research Papers
954 drug discovery papers about Multiple system atrophy, with 5 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
954 drug discovery papers about Multiple system atrophy, with 5 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | Risk of drug-induced liver injury in multiple system atrophy patients treated with KM-819 is potentially associated with the HLA-DPB1*05:01:01:01 allele.
KM-819, a first-in-class inhibitor of Fas-associated factor 1 (FAF1), was investigated in a Phase 2 clinical trial in Korean patients with multiple system atrophy (MSA). Among 34 KM-819-treated patients, 11 met the case definition for suspected DILI, and 9 of these (26%) were adjudicated by an independent hepatic adjudication committee (HAC) as KM-819-related DILI; no cases occurred among the 34 patients receiving placebo. Blood samples for genetic analysis were available from only 6 of the 9 adjudicated DILI cases; therefore, an exploratory comparative genetic analysis was performed using DNA samples from a total of 16 patients treated with KM-819, including the 6 available DILI cases and 10 patients without DILI. Whole-genome sequencing (WGS) identified the HLA-DPB1*05:01:01:01 allele in all 6 patients with DILI, compared to only 1 of the 10 patients without DILI (p = 0.0009), suggesting a potential association between HLA-DPB1*05:01:01:01 and DILI due to KM-819. In this discovery cohort, HLA-DPB1*05:01:01:01 showed 100% sensitivity, 90.0% specificity, a positive predictive value (PPV) of 85.7%, and a negative predictive value (NPV) of 100% for DILI due to KM-819, albeit with wide confidence intervals reflecting the small sample size. Given the small sample size, exploratory nature of the analysis, and use of the same cohort for both discovery and performance estimation, these findings should be considered hypothesis-generating. Therefore, HLA-DPB1*05:01:01:01 should be regarded as a candidate risk marker specific to this Korean cohort, requiring validation in larger, independent, and ethnically diverse cohorts before its application in clinical risk stratification.
2026-09-25 | Breaking the proteasome balance: α-synuclein and the ubiquitin-proteasome system.
Aging is the major risk factor for synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. However, the molecular mechanisms linking aging to. α-Synuclein cytotoxicity remain incompletely understood. The progressive decline of proteostasis is central among these mechanisms, as the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway fail to maintain the turnover of aggregation-prone proteins. In this review, we focus on the bidirectional crosstalk between α-Synuclein and the proteasome as a key driver of proteostasis collapse in synucleinopathies. Proteasome activity declines during aging, and proteasomal dysfunction is closely associated with disease progression. We first discuss how. α-Synuclein structure and posttranslational modifications determine whether the protein is targeted for degradation by the UPS or autophagy or instead acts as a proteolytic inhibitor. Next, the mechanisms by which pathogenic α-synuclein species interact with and impair 20S/26S proteasomes, affecting proteolytic activity, subunit composition, and complex assembly, are discussed. These interactions establish a self-amplifying cycle of proteasome inhibition and α-Synuclein accumulation. As a consequence, the cellular capacity to clear misfolded proteins progressively declines, promoting toxic α-Synuclein aggregation and neurodegeneration. We further discuss the importance of autophagy on α-Synuclein turnover and how this is impaired in synucleinopathies. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function and proteostasis. A deeper understanding of how α-Synuclein-proteasome interactions change during ageing may reveal new molecular targets and support the development of disease-modifying therapies for synucleinopathies.
2026-09-19 | Serum Metabolomic Profiles Unveil Biomarkers and Core Metabolic Pathways in Multiple System Atrophy Patients.
Multiple system atrophy (MSA) is an adult-onset, fatal, neurodegenerative disease lacking mechanistic understanding, early diagnosis, and specific treatments. Metabolomics has been widely used in neurodegenerative diseases for biomarker identification and pathophysiology exploration; however its application in MSA is extremely limited. To investigate the metabolomic landscape, core metabolic pathways, and novel biomarkers for MSA. Untargeted metabolomics (ultra-high-performance liquid chromatography-Q-Exactive HF mass spectrometry [UHPLC-QE-MS]) was performed on serum samples from 85 MSA patients and 85 healthy controls (HCs). Candidate metabolites were validated via targeted metabolomics in an internal cohort (37 MSA, 36 HCs) and an external cohort (44 MSA, 44 Parkinson's disease [PD], 42 HCs). In vitro validation was performed using MO3.13 cells and SH-SY5Y cells overexpressing hSNCA. We identified 112 and 70 differential metabolites (DMs) in positive and negative modes, respectively. Pathway analysis revealed six significant pathways, including arginine and proline metabolism; pentose phosphate pathway; valine, leucine, and isoleucine biosynthesis; purine metabolism; arginine biosynthesis; and riboflavin metabolism. A riboflavin-xanthine panel effectively distinguished MSA from HCs (internal validation: [area under the curve [AUC] = 0.876), and this performance was confirmed in the external cohort (AUC = 0.943). Reduced xanthine levels in MSA patients compared with HCs and PD patients slightly enhanced the diagnostic power of neurofilament light chain for MSA-PD differentiation, boosting the AUC from 0.821 to 0.890. Both riboflavin and xanthine supplementation enhanced viability and reduced apoptosis in hSNCA-overexpressing MO3.13 cells, while only riboflavin exerted therapeutic effects in hSNCA-overexpressing SH-SY5Y cells. This study defined the serum metabolomic signature of MSA and highlighted novel biomarkers, pathological mechanisms, and therapeutic targets deserving further validation. © 2026 International Parkinson and Movement Disorder Society.
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.
2026-09-08 | REM sleep behavior disorder and synucleinopathies.
Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD) is a somnipathy characterized by a physiological failure of skeletal muscle atonia during REM sleep. Such a brainstem pathway disruption, which directly affects the pontomedullary reticular formation, disrupts the descending inhibitory pathways that normally cause muscle paralysis. Patients then are much more likely to act out their dreams and will have complex, often violent dream-enactment behaviors that may cause injury and disrupt sleep continuity. Almost two decades of research have shown that RBD is potentially a crucial early indicator for synucleinopathies (brain diseases that are related to the accumulation of alpha-synuclein protein). These diseases include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Emerging biomarkers, neuroimaging results, and fluid-based biomarkers are discussed in the context of risk stratification and prediction of phenotypic pathophysiological transformation to overt neurodegenerative disease. Moreover, the chapter discusses how RBD provides a window for testing neuroprotective and disease-modifying therapies that may delay or prevent overt synucleinopathy. It also reviews current symptom management approaches that mix pharmacological treatment with non-pharmacological safety measures for injury prevention and neuromodulation technologies that target disrupted motor circuitry. Understanding the relationship between RBD and synucleinopathies offers a unique window into the earliest stages of neurodegeneration and presents new possibilities for early diagnosis, targeted treatment, and better patient outcomes.
proteins
2026-07-25 | Multiple system atrophy: cure and care.
Multiple system atrophy (MSA) is a rare and rapidly progressive neurodegenerative disorder characterized by a variable combination of autonomic failure, parkinsonism, and cerebellar ataxia, with a median survival of 8-10 years from symptom onset. Its aetiology remains poorly understood, as most cases are sporadic and environmental contributors remain unclear. Neuropathologically, MSA is defined by the accumulation of α-synuclein within oligodendroglial cells, forming glial cytoplasmic inclusions that drive widespread neurodegeneration in striatonigral and olivopontocerebellar systems. Recent advances in diagnostic criteria and biomarker development have improved disease recognition; however, early diagnosis remains challenging, particularly during the prodromal phase, when clinical features overlap with other α-synucleinopathies. Advances in fluid biomarkers and multimodal imaging are expected to facilitate earlier detection, improve diagnostic accuracy, and provide more robust tools for monitoring disease progression. Therapeutic development has largely focused on targeting α-synuclein pathology, but these approaches have not yet demonstrated consistent clinical benefit, highlighting the biological complexity of MSA. In the absence of curative treatments, management remains largely supportive, aimed at symptom control, particularly addressing autonomic dysfunction and motor impairment. Emerging care models, including telemedicine and multidisciplinary management, are reshaping clinical practice and may improve access to specialized care. Bridging advances in pathophysiology with patient-centred care will be essential for improving outcomes in MSA.
2026-07-03 | Opsoclonus revealing underlying multiple system atrophy: a case report.
Delayed emergence from general anesthesia has multiple etiologies; in rare cases, it may unmask an unrecognized neurodegenerative disorder. A 64-year-old man underwent laparoscopic cholecystectomy under general anesthesia. No neurological abnormalities were identified preoperatively. After surgery, response to verbal stimuli was inadequate; however, other extubation criteria were met and he was extubated. Approximately 45 min later, rapid nystagmus-like eye movements consistent with opsoclonus developed, initially oscillating horizontally and then vertically, and persisted for about six minutes. A similar episode recurred 125 min after extubation. Head computed tomography showed no acute lesions but revealed marked cerebellar and brainstem atrophy. Subsequent neurological evaluation, including magnetic resonance imaging demonstrating the "hot cross bun" sign, fulfilled the Movement Disorder Society diagnostic criteria for clinically established multiple system atrophy with predominant parkinsonism. In unexplained delayed emergence from general anesthesia, opsoclonus should prompt evaluation for an underlying neurodegenerative disorder.
2026-06-26 | Effects of Environmental Arsenic Exposure on the Morphology of Multiple Organs in Female Mice During Pre-Pregnancy, Gestation, and Lactation.
To investigate the effects of environmentally relevant arsenic (As) exposure on multiple organs (liver, kidney, spleen, ovary, and uterus) in female mice during pre-pregnancy, gestation, and lactation, and to clarify the critical time window associated with As-induced organ toxicity. As exposure models (0.02, 0.1, or 0.5 mg/L As2O3) were established for mice during pre-pregnancy, gestation, and lactation. Meanwhile, the effects on the fertility of female mice, blood parameters, and pathological changes of the liver, kidneys, spleen, ovaries and uterus of the exposed mice were evaluated. Additionally, a marker of DNA-strand break (γH2AX) and apoptosis (TUNEL) was assessed in the liver and kidney during gestation and lactation. The findings indicated that As exposure during these stages did not impair fertility in female mice. However, exposure to 0.5 mg/L As2O3 during gestation caused reductions in red blood cells (RBC), hemoglobins (HGB), and platelets (PLT). Meanwhile, hepatic lipid levels was increased in mice exposure to 0.1 mg/L As2O3 during gestation, and mice exposed to 0.1 mg/L As2O3 during lactation exhibited glomerular atrophy and hepatocyte vacuolization. In addition, mice exposed to 0.5 mg/L As2O3 during both gestation and lactation exhibited varying degrees of inflammatory cell infiltration in both the liver and kidney. Notably, γH2AX was elevated in the kidneys at 0.1 and 0.5 mg/L As2O3 during gestation and lactation, whereas no change was observed in the liver. TUNEL staining revealed no obvious alterations in either organ throughout this period. These observations suggest that females may be more vulnerable to As during gestation and lactation, with the liver and kidney serving as primary sites of toxicity accumulation.
2026-06-22 | Glucagon-like peptide-1 receptor agonists in movement disorders: From Parkinson's disease to the broader spectrum - Mechanisms, evidence, and future directions.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and obesity, have emerged as potential neuroprotective agents in neurodegenerative disorders. GLP-1 signaling modulates key pathogenic pathways relevant to movement disorders, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired proteostasis, with receptors widely expressed in motor-related brain regions. This narrative reviewaimed to summarize current mechanistic, preclinical, and clinical evidence regarding the role of GLP-1RAs across the spectrum of movement disorders. A narrative review of the literature was conducted, including preclinical studies, randomized clinical trials, observational data, and pharmacovigilance analyses evaluating GLP-1RAs in movement disorders. Preclinical studies consistently demonstrate neuroprotective effects of GLP-1RAs, including preservation of dopaminergic neurons, reduction of α-synuclein aggregation, and improvement in motor function. Clinical evidence is most advanced in Parkinson's disease, where early randomized trials of exenatide and lixisenatide suggested modest motor benefits and possible disease-modifying effects. However, subsequent larger studies, including the phase III Exenatide-PD3 trial, failed to demonstrate significant clinical benefit. Preliminary signals have been reported in multiple system atrophy, whereas evidence in Huntington's disease, essential tremor, and other movement disorders remains largely preclinical. GLP-1RAs represents a biologically plausible but as yet unproven disease-modifying strategy in movement disorders. Translational challenges, including pharmacologic heterogeneity, variability in central nervous system exposure, and clinical trial design limitations-must be addressed. Future research should focus on biomarker-guided patient selection, optimized CNS-penetrant agents, and rigorously designed clinical trials.
2026-04-20 | Subjects Affected by Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) Elevated Brain-Derived Neurotrophic Factor (BDNF) Serum Levels.
Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) are neurodegenerative disorders with marked neuronal dysfunction and damage, accompanied by the accumulation of abnormal alpha-synuclein. Identifying the proteins involved in their specific neurodegenerative processes is important to understand shared or disease-specific mechanisms of neurodegeneration. Recent investigations into these disorders have revealed intriguing alterations in the functionality of neurotrophic factors, including and predominantly the Brain-Derived Neurotrophic Factor (BDNF). Thus, the aim of this study was to investigate the BDNF serum levels in two cohorts of DLB and MSA patients and compare them to those of healthy individuals. Investigating serum BDNF concentrations in these conditions may provide insights into aspects of the underlying mechanisms of neurodegeneration. Serum BDNF concentrations were determined using commercial enzyme-linked immunosorbent assays. All serum samples were tested in duplicate, and the reported BDNF concentrations were ng/ml. The findings demonstrated a significant increase in serum BDNF levels in both DLB and MSA patients versus healthy subjects. This increase may represent a compensatory neuroprotective response to ongoing neuronal damage or a reflection of disease-related pathophysiological mechanisms involving altered BDNF regulation. These findings contribute to a growing body of evidence implicating neurotrophic fac-tor dysregulation in the pathogenesis of α-synucleinopathies. Moreover, the findings highlight BDNF as a potential therapeutic target and a candidate adjunct biomarker for diagnosis, monitoring disease activity, or treatment response. Additional experiments will clarify this causal relationship and the utility of BDNF-based interventions in modifying the disease trajectories in DLB and MSA.
cell therapies
2026-09-21 | CD8+ T cells in synucleinopathies: differential immune mechanisms in Parkinson's disease and multiple system atrophy.
Synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA), are characterized by α-synuclein aggregation and progressive neurodegeneration. Increasing evidence implicates adaptive immune mechanisms, particularly CD8+ T cells, in their pathogenesis. To summarize and compare the role of CD8+ T lymphocytes in PD and MSA, with an emphasis on disease-specific immune mechanisms. A structured narrative review of PubMed, Embase, and Scopus databases was performed, and 15 relevant studies were included. In PD, CD8+ T cells infiltrate the substantia nigra at early disease stages, often preceding overt neurodegeneration and α-synuclein deposition, and exhibit a cytotoxic phenotype characterized by granzyme and interferon-γ expression, with potential direct interactions with MHC class I-expressing neurons. Peripheral findings further support a CD8-dominant immune response with expansion of cytotoxic subsets. In contrast, MSA is associated with a relatively CD4-dominant immune profile, with increased CD4/CD8 ratios and a broader inflammatory environment, in which CD8+ T cells appear to play a more modulatory role. Across synucleinopathies, CD8+ T cells demonstrate regional CNS infiltration, phenotypic heterogeneity, and association with microglial activation. CD8+ T cells represent a heterogeneous and context-dependent component of adaptive immunity in synucleinopathies, with a predominantly cytotoxic and potentially pathogenic role in PD and a more modulatory function in MSA. These disease-specific d ifferences pr ovide in sight in to un derlying ne uroimmune me chanisms an d su pport th e po tential of CD8+ T-cell-related pathways as biomarkers and targets for tailored immunomodulatory strategies.
2026-04-06 | Safety and Efficacy of Mesenchymal Stem Cell Therapy in Multiple System Atrophy: Systematic Review.
To systematically evaluate the efficacy and safety of mesenchymal stem cell (MSC) therapy for patients with Multiple System Atrophy (MSA) by synthesising available clinical trial evidence and clarifying signals of disease modification. MSA is a rapidly progressive and fatal neurodegenerative disorder for which no disease-modifying therapies exist. MSC therapy has emerged as a potential treatment, with mechanisms centered on neuroprotection and clinical benefit through anti-inflammatory and trophic effects rather than direct cell replacement. We systematically searched PubMed, Scopus, the Cochrane Library, and Web of Science for studies on mesenchymal stem cell (MSC) therapy in adults with probable or confirmed multiple system atrophy (MSA). Eligible studies included single-arm trials or comparisons with placebo or usual care. The primary outcome was safety and tolerability, assessed by the type and severity of adverse events. Secondary outcomes included the rate of disease progression measured by UMSARS total, Part I, and Part II scores. A total of 123 participants from seven studies were included. MSCs were administered through multiple routes, and adverse events occurred in 65-70% of participants but were mostly mild and transient. No serious MSC-related toxicity was reported. Several studies suggested slower disease progression following MSC therapy. For example, in Singer et al (2019), patients receiving high-dose MSCs showed a markedly lower rate of UMSARS total score progression compared with a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004), suggesting a possible dose-dependent effect. However, treatment effects varied across studies depending on dose, administration route, and disease stage. MSC therapy shows potential for disease modification in MSA by slowing neurological deterioration. The treatment was well tolerated, supporting the need for larger, definitive trials with standardised protocols and longer follow-up to confirm clinical benefit.
2026-03-30 | Cytotoxic T cell recognition of α-synuclein drives pathogenic immune responses in multiple system atrophy.
Multiple system atrophy (MSA) is a progressive neurologic disease, known as an α-synucleinopathy. There are currently no effective disease-modifying therapies for MSA. While neuroinflammation is a hallmark of MSA, the contribution of adaptive immune mechanisms remains poorly understood. Here, we profiled peripheral and central T cell responses in patients with MSA, in comparison with Parkinson's disease (PD) and healthy control cohorts, using single-cell transcriptomics, flow cytometry, and antigen-specific functional assays. We demonstrated that peripheral T cells from MSA patients are activated and skewed toward cytotoxic and inflammatory phenotypes. Single-cell transcriptomics further revealed clonal expansion of cytotoxic CD8+ T cells expressing GZMB, GNLY, and chemokine and integrin programs associated with brain homing. We also demonstrated that both CD4+ and CD8+ T cells from MSA patients recognize α-synuclein monomers and preformed fibrils in an HLA class I/II-dependent manner, driving proliferation, clonal expansion, and acquisition of cytotoxic features. Consistent with these peripheral responses, CD8+ T cell density was increased in the parietal cortex of postmortem MSA brain tissues, along with cytotoxic (GZMB+, GZMK+) and proinflammatory (IFNγ+) CD8+ T cells. Together, these findings demonstrate that cytotoxic T cells targeting α-synuclein are engaged in MSA, suggesting that their activity may contribute to neuroinflammation and disease progression, and highlighting this immune axis as a candidate therapeutic target for further investigation.
2024-11-26 | Human Umbilical Cord Blood-Mononuclear Cell Transplantation Improves Glymphatic System Activity in Patients with Multiple System Atrophy
Motivation: Glymhatic system as a therapeutic target for multiple system atrophy (MSA) lacks imaging markers. Goal(s): Our goal was to determine changes in imaging parameters after human umbilical cord blood mononuclear cells (hUCB-MCs) transplantation. Approach: Diffusion tensor image analysis along the perivascular space (DTI-ALPS) of MSA patients were compared with healthy controls and the ALPS indices of patients were compared before and after hUCB-MCs transplantation. Results: We found that MSA patients had lower ALPS values than health controls and that ALPS values increased after treatment. Impact: Our demonstration of a detectable decline in MSA patients and an uptick after treatment utilizing ALPS metrics provides an imaging marker to monitor the glymphatic system after hUCB-MCs transplantation.
2024-09-11 | Evolving insights into erythrocytes in synucleinopathies.
Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are characterized by neuronal loss accompanied by α-synuclein (α-syn) accumulation in the brain. While research conventionally focused on brain pathology, there is growing interest in peripheral alterations. Erythrocytes, which are rich in α-syn, have emerged as a compelling site for synucleinopathies-related alterations. Erythrocyte-derived extracellular vesicles (EVs), containing pathological α-syn species, can traverse the blood-brain barrier (BBB) under certain conditions and the gastrointestinal tract, where α-syn and gut microbiota interact extensively. This review explores the accumulating evidence of erythrocyte involvement in synucleinopathies, as well as their potential in disease pathogenesis and diagnosis. Given their unique properties, erythrocytes and erythrocyte-derived EVs may also serve as an ideal therapeutic platform for treating synucleinopathies and beyond.
gene therapies
2026-04-03 | Urogenital dysfunction in neurological diseases.
Neural damage at any level of the neuraxis can lead to urogenital dysfunction, involving the lower urinary tract (LUT) and/or the sexual organs. The LUT consists of the bladder and the urethra (plus the prostate in males); LUT dysfunction can manifest as an underactive bladder, leading to urinary retention, or as an overactive bladder, leading to urinary incontinence. Manifestations of sexual dysfunction include loss of libido and dysfunction of erection, ejaculation and orgasm. In this Review, we address the physiology and innervation of the LUT and the sexual organs and discuss various aspects of urogenital dysfunction in CNS (brain and spinal cord) disorders including stroke, Alzheimer disease, white matter disease, normal-pressure hydrocephalus, Parkinson disease, dementia with Lewy bodies, multiple system atrophy, spinal cord injury, multiple sclerosis and spina bifida. We also review advances in the management of urogenital dysfunction in patients with neurological disorders.
2026-03-12 | Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.
The aggregation of the protein alpha-synuclein (αSyn) is a common feature of multiple neurodegenerative diseases collectively called synucleinopathies, for which the pathobiology is not well understood. The different phenotypic characteristics of the synucleinopathies Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) have been proposed to originate from the distinct structures adopted by αSyn in its amyloid forms. Here, using covalent labeling and limited proteolysis coupled to mass spectrometry (LiP-MS) in vitro and in situ within neuronal cells and directly in native patient brain homogenates, we show that pathogenic αSyn from distinct synucleinopathies (PD, DLB and MSA) are structurally different. Further, we found that fibril structural differences are associated with different putative fibril interactomes and neuronal responses. We discovered disease-specific ubiquitination patterns and turnover profiles for pathogenic αSyn species, detected molecular pathways responding specifically to the uptake of different αSyn fibrillar polymorphs, and identified a subset of the involved proteins as putative interactors of αSyn. In particular, components of the ubiquitin-proteasomal System (UPS), including E3 ubiquitin ligases, chaperones, and deubiquitinating proteins, showed disease/polymorph-specific putative interaction patterns, possibly accounting for different resistance of patient-derived αSyn fibrils to degradation. Genetic modulation with CRISPR-based tools showed that members of the UPS degradation pathway (three E3 ligases: UBE3A, TRIM25, HUWE1 and the AAA+ ATPase VCP) reduced αSyn inclusions, in a strain-specific manner. LiP-MS also identified sets of proteins with altered protease susceptibility in postmortem brain homogenates of PD, DLB, and MSA patients. These sets were largely disease-specific and included proteins altered in cells treated with fibrils derived from patients with the matching disease. Our findings provide insight into cellular processes involved in the accumulation and turnover of αSyn pathogenic aggregates in PD, DLB and MSA in a disease/specific manner and constitutes a resource of potential novel drug targets in these synucleinopathies.
2026-02-27 | Metabolomics of Multiple System Atrophy Patient-Derived Striatal Medium Spiny Neurons.
In multiple system atrophy (MSA), the fatal movement disorder, cell populations of the striatum and other subcortical brain regions degenerate, leading to a rapidly progressive, atypical Parkinsonian syndrome. The pathophysiology of neurons and glial cells shows misfolding, aggregation, and increased release of the protein α-synuclein. In addition, neuronal hypoexcitability, a reduction in the activity of the mitochondrial respiratory chain, and a dysregulation of the enzymes involved in the biosynthesis of coenzyme Q10 were observed in human stem-cell models. In this study, untargeted and targeted metabolome analyses were performed with MSA patient-derived GABAergic striatal medium spiny neurons focusing on the citrate cycle and mitochondrial respiratory chain. The results indicate a significant decrease in succinate and ATP as well as an imbalanced NAD+/NADH ratio of MSA cell lines compared to matched healthy controls, suggesting alterations in mitochondrial processes which may facilitate neurodegeneration.
2026-02-21 | Accuracy of clinical diagnosis in neurodegenerative diseases - a study of 455 autopsy cases.
Precision of clinical diagnosis in neurodegenerative diseases is critically important for clinical care and study recruitment. This study aimed to investigate the clinical accuracy using gold-standard neuropathological reference. Neuropathological diagnoses from the Neurobiobank München were correlated with real-world clinical diagnoses from hospitals in Germany. Accuracy metrics, including sensitivity, specificity, and area under the curve (AUC) of clinical diagnoses, were calculated. Among nine neuropathologically diagnosed neurodegenerative diseases (Alzheimer's disease, argyrophilic grain disease, corticobasal degeneration, frontotemporal lobar degeneration, Huntington's disease, Lewy body disease, motor neuron disease, multiple system atrophy, and progressive supranuclear palsy) with a total of 455 cases, clinical sensitivity varied widely (0-100%) whereas specificity was consistently high (89.5-100%). Accuracy was very good (AUC > 0.9) for Huntington's disease, motor neuron disease, and multiple system atrophy; good (AUC = 0.8-0.9) for Alzheimer's disease, dementia with Lewy bodies/Parkinson's disease, and progressive supranuclear palsy; moderate (AUC = 0.7-0.8) for frontotemporal dementia, limited (AUC = 0.51-0.7) in the n = 20 cases with corticobasal degeneration, and no discriminatory capacity (AUC = 0.5) in the n = 6 cases with argyrophilic grain disease. Clinical diagnostic accuracy of neurodegenerative diseases varies, with sensitivity as the main limiting factor. Improving diagnostic sensitivity will be essential for early and accurate patient identification, especially as disease-modifying therapies targeting causal proteinopathies become available. Achieving this will depend on the development and clinical implementation of reliable molecular biomarkers that indicate the causal proteinopathies of neurodegenerative diseases.
2026-01-17 | Association of choroid plexus volume with brain atrophy and glucose metabolism in multiple system atrophy.
The choroid plexus (CP), a component of the glymphatic system, is essential in homeostasis and producing cerebrospinal fluid. Role of CP in multiple system atrophy (MSA) remains unclear. This study aimed to investigate the implication of the CP in MSA. This retrospective cross-sectional study included 87 MSA patients who underwent the Unified MSA Rating Scale (UMSARS), brain MRI, and18F-fluorodeoxyglucose PET scan, along with 84 healthy controls (HCs). Multivariate linear regression analyses were performed to examine the associations between CP volume (CPV) and UMSARS scores, as well as the volumes and cerebral metabolism. Compared with HCs, MSA had significantly reduced CPV (1.00 ± 0.27 vs. 1.30 ± 0.26, P < 0.001). CPV showed no association with UMSARS, however, it was positively correlated with regional cerebellar volumes. Reduced CPV was associated with lower cerebral glucose metabolism in MSA-susceptible regions, consistent with the positive association between CPV and regional cerebral glucose metabolism observed in multivariate analyses. Notably, CPV positively correlated with glucose metabolism in the brainstem (β = 0.110, P = 0.003) and cerebellar white matter (β = 0.080, P = 0.004). This study suggests that CPV is positively associated with disease burden in MSA, with CPV decreasing as disease severity increases. Further research is warranted to determine whether CPV could serve as a potential biomarker for MSA.
other
2026-08-05 | A single-domain antibody targets aggregation-prone region of α-synuclein to reduce synucleinopathy, rescue neurodegeneration and improve function.
Synucleinopathies are a group of neurodegenerative disorders characterized by the accumulation of aggregated α-synuclein (α-syn), including Parkinson's disease, Dementia with Lewy Bodies, and Multiple System Atrophy. These diseases are marked by locomotor and non-motor impairments, as well as mitochondrial dysfunction and the loss of dopaminergic (DA) neurons. We have developed several anti-α-syn single-domain antibodies (sdAbs) and demonstrated the diagnostic imaging potential of two of them and the acute therapeutic benefit of one in clearing α-syn in a mouse model. However, whether these sdAbs can suppress α-syn-mediated neuronal loss and locomotor impairment in vivo remains unclear. We evaluated the therapeutic potential of five anti-α-syn sdAbs to clear pathological α-syn in mouse neuronal culture and then demonstrated their in vivo efficacy in a Drosophila model of synucleinopathy. The sdAbs differed in their efficacy to lower levels of phospho-serine 129 α-syn, prevent loss of DA neurons, alleviate mitochondrial dysfunction, improve motor function, and prolong survival in synucleinopathy flies. The most effective sdAb, 2H1, has not been reported before. It binds strongly to the aggregation prone region of α-syn and robustly improves all these disease parameters. Additionally, that sdAb is associated with α-syn in the fly neurons, as shown through proximity dependent turboID biotinylation assays. The sdAb-turboID also biotinylated α-syn-associated proteins involved in synapse/vesicle trafficking pathways, pinpointing the location of their intracellular interaction. Our findings provide an insight into the therapeutic mechanism of action of these sdAbs and strongly support their clinical development.
2026-07-16 | Development of an RNA aptamer as a therapeutic agent for synucleinopathies.
The aggregation of α-synuclein (αSyn), a 140-mer protein, has been implicated in the pathogenesis of Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. KTKEGV pseudo-repeats (KRs) in the sequence of αSyn are key mediators of its prion-like propagation and neurodegeneration. Despite the availability of symptomatic treatments, no current therapy effectively delays disease progression. Here we report a 77-nucleotide RNA aptamer called 1R6, obtained through in vitro selection, that binds with high affinity and selectivity to αSyn1-95. 1R6 significantly inhibits αSyn oligomerization and β-sheet-rich fibril assembly and promotes disaggregation of preformed fibrils. Additionally, 1R6 suppresses αSyn seeding, as determined by a FRET-based biosensor-cell assay. Cellular studies reveal that 1R6 co-transfection completely prevents αSyn-induced cytotoxicity. To assess the protective effects of 1R6 in vivo, we use a Drosophila melanogaster model expressing human αSyn in neurons. Flies fed 1R6 show improved locomotor activity, reduced photoreceptor degeneration, and decreased αSyn levels in the head. Structural characterization using 1H-15N heteronuclear multiple quantum correlation nuclear magnetic resonance experiments demonstrates that 1R6 targets KR motifs, a finding further supported by in silico simulations. Our findings support further development of RNA aptamers, such as 1R6, including evaluation of efficacy, stability, delivery, and immune responses in mammalian systems, highlighting their potential as therapeutic candidates for synucleinopathies.
2026-06-19 | Sex-Dependent Effects of CSF1R-Mediated Myeloid Cell Depletion in a Mouse Model of Multiple System Atrophy.
Sex-dependent differences in neurodegenerative disorders are becoming increasingly relevant in diagnosis and development of therapeutic targets. Although multiple system atrophy (MSA), a devastating and rapidly progressing atypical parkinsonian disorder, is distributed equally among sexes, sex-specific differences have been reported regarding autonomic dysfunctions, severity of motor symptoms, and survival rate, suggesting a need for sex-specific treatment approaches. Neuroinflammation is a prominent hallmark in MSA pathology. Distinct activation patterns and increased phagocytosis of central nervous system (CNS) myeloid cells were observed, indicating a damaging role in this disease. In our previous study, we showed that colony-stimulating factor 1 receptor (CSF1R)-mediated depletion of myeloid cells in a mouse model of MSA led to a two-faced outcome, comprised of a prolonged survival and delayed onset of neurological dystonia-like symptoms, but also an aggravated motor phenotype and loss of dopaminergic neurons. Here, we re-analyzed our previous findings to study sex-specific effects in MSA in the presence and absence of CNS myeloid cells. Intriguingly, myeloid cell depletion was initially more effective in male animals. Although no sex-specific effects were detected in motor behavior, the occurrence of dystonia-like neurological symptoms was reduced, and neuronal loss was alleviated in male animals. Together, our findings provide insight into sex-specific differences of CSF1R-mediated myeloid cell depletion in MSA, emphasizing the need to study sex-specific treatment strategies in neurodegenerative disorders.
2026-05-15 | Systemic delivery of anti-sense oligonucleotide targeting α-synuclein for treatment in a mouse model of multiple system atrophy.
Multiple System Atrophy (MSA) is a rare, sporadic, age-related synucleinopathy characterized by Parkinson-like motor symptoms and ataxia. There is no therapy for MSA other than symptomatic treatment. MSA is characterized pathologically by glial cytoplasmic inclusions (GCI) of α-synuclein (αSyn) occurring in oligodendrocytes leading to loss of myelination in the brain. We recently utilized a peptide-mediated delivery method to systemically transport an anti-sense oligonucleotide (ASO) targeted to αSyn in a mouse model of MSA. We hypothesized that systemic delivery of αSyn ASO by peptide mediated delivery to a mouse model of MSA would reduce the αSyn accumulation in oligodendrocytes and reduce the overt pathology associated with MSA. Following monthly treatments of the αSyn ASO, we found increased myelination in the corpus callosum, cerebellum and brainstem. We also observed increased numbers of oligodendrocytes and reduced gliosis; however, we did not detect changes in overall αSyn in the areas of the brain we examined. Upon further analysis, we determined the peptide-mediated delivery of αSyn ASO was not taken up by oligodendrocytes. Thus, we have successfully alleviated some of the pathology associated with MSA in a mouse model; however, without direct delivery to oligodendrocytes, other approaches may need to supplement this therapy.
2026-04-28 | Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial.
Pathological aggregation and propagation of α-synuclein species drive disease progression in multiple system atrophy (MSA). We assessed the efficacy and safety of amlenetug, a monoclonal antibody targeting aggregated α‑synuclein, versus placebo in slowing clinical disease progression in people with MSA. We did a randomised, controlled, parallel-group trial (AMULET) at 18 movement disorder and autonomic dysfunction specialist sites across the USA and Japan. Patients aged 40-75 years with MSA who had motor symptom onset in the past 5 years were randomly assigned (2:1) to intravenous amlenetug or placebo every 4 weeks for 48-72 weeks in a common close design. Randomisation was performed via an interactive response system, stratified by region and blood neurofilament light chain concentration, using a block size of three. The double-blind treatment period ended when the last randomised participant had concluded the week 48 visit. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment allocation. The primary endpoint was disease progression, assessed using a Bayesian progression model of the longitudinal changes from baseline in the Unified Multiple System Atrophy Rating Scale (UMSARS) total (parts I and II) score up to week 72, in all participants who had a valid baseline assessment and at least one valid post-baseline assessment of UMSARS total score. Safety was assessed in all treated participants. This trial is registered at ClinicalTrials.gov (NCT05104476); the open-label phase of the trial is ongoing. Between Nov 16, 2021, and Oct 6, 2022, 91 unique participants were screened, of whom 64 were randomly assigned and 61 received treatment (amlenetug n=40; placebo n=21). Among treated participants, mean age was 60·8 years (SD 7·7); 32 (52%) were male and 29 (48%) female. 48 (79%) of 61 participants completed double-blind treatment (mean 56 weeks [SD 13] treatment). The Bayesian probability of 89·4% for a true slowing of clinical disease progression did not reach the predefined threshold of 97·5%, and accordingly, the primary endpoint was not met. The effect parameter of 0·81 (2·5th to 97·5th percentile 0·56 to 1·13) equates to a non-significant slowing of clinical progression by 19% (2·5th to 97·5th percentile -13 to 44) for amlenetug versus placebo. Amlenetug was generally well tolerated, with comparable rates of treatment‑emergent adverse events (n=40 [100%] with amlenetug vs n=20 [95%] with placebo) and serious treatment‑emergent adverse events (n=12 [30%] vs n=7 [33%]). The most common treatment-emergent adverse events were COVID‑19 infection (n=11 [28%] vs n=5 [24%]), back pain (n=6 [15%] vs n=2 [10%]), headache (n=5 [13%] vs n=1 [5%]), urinary tract infection (n=4 [10%] vs n=3 [14%]), peripheral oedema ([n=4] 10% vs n=1 [5%]), flushing (n=4 [10%] vs 0), and hypertension (n=4 [10%] vs 0). Two deaths occurred in each group, with only one death, in the placebo group, considered possibly treatment related. Although the trial did not meet its primary endpoint, the statistically non-significant finding of potentially slowed clinical progression, together with an acceptable safety profile, supported further evaluation in a phase 3 trial. H Lundbeck.
small molecules
2026-09-29 | Risk of drug-induced liver injury in multiple system atrophy patients treated with KM-819 is potentially associated with the HLA-DPB1*05:01:01:01 allele.
KM-819, a first-in-class inhibitor of Fas-associated factor 1 (FAF1), was investigated in a Phase 2 clinical trial in Korean patients with multiple system atrophy (MSA). Among 34 KM-819-treated patients, 11 met the case definition for suspected DILI, and 9 of these (26%) were adjudicated by an independent hepatic adjudication committee (HAC) as KM-819-related DILI; no cases occurred among the 34 patients receiving placebo. Blood samples for genetic analysis were available from only 6 of the 9 adjudicated DILI cases; therefore, an exploratory comparative genetic analysis was performed using DNA samples from a total of 16 patients treated with KM-819, including the 6 available DILI cases and 10 patients without DILI. Whole-genome sequencing (WGS) identified the HLA-DPB1*05:01:01:01 allele in all 6 patients with DILI, compared to only 1 of the 10 patients without DILI (p = 0.0009), suggesting a potential association between HLA-DPB1*05:01:01:01 and DILI due to KM-819. In this discovery cohort, HLA-DPB1*05:01:01:01 showed 100% sensitivity, 90.0% specificity, a positive predictive value (PPV) of 85.7%, and a negative predictive value (NPV) of 100% for DILI due to KM-819, albeit with wide confidence intervals reflecting the small sample size. Given the small sample size, exploratory nature of the analysis, and use of the same cohort for both discovery and performance estimation, these findings should be considered hypothesis-generating. Therefore, HLA-DPB1*05:01:01:01 should be regarded as a candidate risk marker specific to this Korean cohort, requiring validation in larger, independent, and ethnically diverse cohorts before its application in clinical risk stratification.
2026-09-25 | Breaking the proteasome balance: α-synuclein and the ubiquitin-proteasome system.
Aging is the major risk factor for synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. However, the molecular mechanisms linking aging to. α-Synuclein cytotoxicity remain incompletely understood. The progressive decline of proteostasis is central among these mechanisms, as the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway fail to maintain the turnover of aggregation-prone proteins. In this review, we focus on the bidirectional crosstalk between α-Synuclein and the proteasome as a key driver of proteostasis collapse in synucleinopathies. Proteasome activity declines during aging, and proteasomal dysfunction is closely associated with disease progression. We first discuss how. α-Synuclein structure and posttranslational modifications determine whether the protein is targeted for degradation by the UPS or autophagy or instead acts as a proteolytic inhibitor. Next, the mechanisms by which pathogenic α-synuclein species interact with and impair 20S/26S proteasomes, affecting proteolytic activity, subunit composition, and complex assembly, are discussed. These interactions establish a self-amplifying cycle of proteasome inhibition and α-Synuclein accumulation. As a consequence, the cellular capacity to clear misfolded proteins progressively declines, promoting toxic α-Synuclein aggregation and neurodegeneration. We further discuss the importance of autophagy on α-Synuclein turnover and how this is impaired in synucleinopathies. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function and proteostasis. A deeper understanding of how α-Synuclein-proteasome interactions change during ageing may reveal new molecular targets and support the development of disease-modifying therapies for synucleinopathies.
2026-09-19 | Serum Metabolomic Profiles Unveil Biomarkers and Core Metabolic Pathways in Multiple System Atrophy Patients.
Multiple system atrophy (MSA) is an adult-onset, fatal, neurodegenerative disease lacking mechanistic understanding, early diagnosis, and specific treatments. Metabolomics has been widely used in neurodegenerative diseases for biomarker identification and pathophysiology exploration; however its application in MSA is extremely limited. To investigate the metabolomic landscape, core metabolic pathways, and novel biomarkers for MSA. Untargeted metabolomics (ultra-high-performance liquid chromatography-Q-Exactive HF mass spectrometry [UHPLC-QE-MS]) was performed on serum samples from 85 MSA patients and 85 healthy controls (HCs). Candidate metabolites were validated via targeted metabolomics in an internal cohort (37 MSA, 36 HCs) and an external cohort (44 MSA, 44 Parkinson's disease [PD], 42 HCs). In vitro validation was performed using MO3.13 cells and SH-SY5Y cells overexpressing hSNCA. We identified 112 and 70 differential metabolites (DMs) in positive and negative modes, respectively. Pathway analysis revealed six significant pathways, including arginine and proline metabolism; pentose phosphate pathway; valine, leucine, and isoleucine biosynthesis; purine metabolism; arginine biosynthesis; and riboflavin metabolism. A riboflavin-xanthine panel effectively distinguished MSA from HCs (internal validation: [area under the curve [AUC] = 0.876), and this performance was confirmed in the external cohort (AUC = 0.943). Reduced xanthine levels in MSA patients compared with HCs and PD patients slightly enhanced the diagnostic power of neurofilament light chain for MSA-PD differentiation, boosting the AUC from 0.821 to 0.890. Both riboflavin and xanthine supplementation enhanced viability and reduced apoptosis in hSNCA-overexpressing MO3.13 cells, while only riboflavin exerted therapeutic effects in hSNCA-overexpressing SH-SY5Y cells. This study defined the serum metabolomic signature of MSA and highlighted novel biomarkers, pathological mechanisms, and therapeutic targets deserving further validation. © 2026 International Parkinson and Movement Disorder Society.
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.
2026-09-08 | REM sleep behavior disorder and synucleinopathies.
Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD) is a somnipathy characterized by a physiological failure of skeletal muscle atonia during REM sleep. Such a brainstem pathway disruption, which directly affects the pontomedullary reticular formation, disrupts the descending inhibitory pathways that normally cause muscle paralysis. Patients then are much more likely to act out their dreams and will have complex, often violent dream-enactment behaviors that may cause injury and disrupt sleep continuity. Almost two decades of research have shown that RBD is potentially a crucial early indicator for synucleinopathies (brain diseases that are related to the accumulation of alpha-synuclein protein). These diseases include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Emerging biomarkers, neuroimaging results, and fluid-based biomarkers are discussed in the context of risk stratification and prediction of phenotypic pathophysiological transformation to overt neurodegenerative disease. Moreover, the chapter discusses how RBD provides a window for testing neuroprotective and disease-modifying therapies that may delay or prevent overt synucleinopathy. It also reviews current symptom management approaches that mix pharmacological treatment with non-pharmacological safety measures for injury prevention and neuromodulation technologies that target disrupted motor circuitry. Understanding the relationship between RBD and synucleinopathies offers a unique window into the earliest stages of neurodegeneration and presents new possibilities for early diagnosis, targeted treatment, and better patient outcomes.
proteins
2026-07-25 | Multiple system atrophy: cure and care.
Multiple system atrophy (MSA) is a rare and rapidly progressive neurodegenerative disorder characterized by a variable combination of autonomic failure, parkinsonism, and cerebellar ataxia, with a median survival of 8-10 years from symptom onset. Its aetiology remains poorly understood, as most cases are sporadic and environmental contributors remain unclear. Neuropathologically, MSA is defined by the accumulation of α-synuclein within oligodendroglial cells, forming glial cytoplasmic inclusions that drive widespread neurodegeneration in striatonigral and olivopontocerebellar systems. Recent advances in diagnostic criteria and biomarker development have improved disease recognition; however, early diagnosis remains challenging, particularly during the prodromal phase, when clinical features overlap with other α-synucleinopathies. Advances in fluid biomarkers and multimodal imaging are expected to facilitate earlier detection, improve diagnostic accuracy, and provide more robust tools for monitoring disease progression. Therapeutic development has largely focused on targeting α-synuclein pathology, but these approaches have not yet demonstrated consistent clinical benefit, highlighting the biological complexity of MSA. In the absence of curative treatments, management remains largely supportive, aimed at symptom control, particularly addressing autonomic dysfunction and motor impairment. Emerging care models, including telemedicine and multidisciplinary management, are reshaping clinical practice and may improve access to specialized care. Bridging advances in pathophysiology with patient-centred care will be essential for improving outcomes in MSA.
2026-07-03 | Opsoclonus revealing underlying multiple system atrophy: a case report.
Delayed emergence from general anesthesia has multiple etiologies; in rare cases, it may unmask an unrecognized neurodegenerative disorder. A 64-year-old man underwent laparoscopic cholecystectomy under general anesthesia. No neurological abnormalities were identified preoperatively. After surgery, response to verbal stimuli was inadequate; however, other extubation criteria were met and he was extubated. Approximately 45 min later, rapid nystagmus-like eye movements consistent with opsoclonus developed, initially oscillating horizontally and then vertically, and persisted for about six minutes. A similar episode recurred 125 min after extubation. Head computed tomography showed no acute lesions but revealed marked cerebellar and brainstem atrophy. Subsequent neurological evaluation, including magnetic resonance imaging demonstrating the "hot cross bun" sign, fulfilled the Movement Disorder Society diagnostic criteria for clinically established multiple system atrophy with predominant parkinsonism. In unexplained delayed emergence from general anesthesia, opsoclonus should prompt evaluation for an underlying neurodegenerative disorder.
2026-06-26 | Effects of Environmental Arsenic Exposure on the Morphology of Multiple Organs in Female Mice During Pre-Pregnancy, Gestation, and Lactation.
To investigate the effects of environmentally relevant arsenic (As) exposure on multiple organs (liver, kidney, spleen, ovary, and uterus) in female mice during pre-pregnancy, gestation, and lactation, and to clarify the critical time window associated with As-induced organ toxicity. As exposure models (0.02, 0.1, or 0.5 mg/L As2O3) were established for mice during pre-pregnancy, gestation, and lactation. Meanwhile, the effects on the fertility of female mice, blood parameters, and pathological changes of the liver, kidneys, spleen, ovaries and uterus of the exposed mice were evaluated. Additionally, a marker of DNA-strand break (γH2AX) and apoptosis (TUNEL) was assessed in the liver and kidney during gestation and lactation. The findings indicated that As exposure during these stages did not impair fertility in female mice. However, exposure to 0.5 mg/L As2O3 during gestation caused reductions in red blood cells (RBC), hemoglobins (HGB), and platelets (PLT). Meanwhile, hepatic lipid levels was increased in mice exposure to 0.1 mg/L As2O3 during gestation, and mice exposed to 0.1 mg/L As2O3 during lactation exhibited glomerular atrophy and hepatocyte vacuolization. In addition, mice exposed to 0.5 mg/L As2O3 during both gestation and lactation exhibited varying degrees of inflammatory cell infiltration in both the liver and kidney. Notably, γH2AX was elevated in the kidneys at 0.1 and 0.5 mg/L As2O3 during gestation and lactation, whereas no change was observed in the liver. TUNEL staining revealed no obvious alterations in either organ throughout this period. These observations suggest that females may be more vulnerable to As during gestation and lactation, with the liver and kidney serving as primary sites of toxicity accumulation.
2026-06-22 | Glucagon-like peptide-1 receptor agonists in movement disorders: From Parkinson's disease to the broader spectrum - Mechanisms, evidence, and future directions.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and obesity, have emerged as potential neuroprotective agents in neurodegenerative disorders. GLP-1 signaling modulates key pathogenic pathways relevant to movement disorders, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired proteostasis, with receptors widely expressed in motor-related brain regions. This narrative reviewaimed to summarize current mechanistic, preclinical, and clinical evidence regarding the role of GLP-1RAs across the spectrum of movement disorders. A narrative review of the literature was conducted, including preclinical studies, randomized clinical trials, observational data, and pharmacovigilance analyses evaluating GLP-1RAs in movement disorders. Preclinical studies consistently demonstrate neuroprotective effects of GLP-1RAs, including preservation of dopaminergic neurons, reduction of α-synuclein aggregation, and improvement in motor function. Clinical evidence is most advanced in Parkinson's disease, where early randomized trials of exenatide and lixisenatide suggested modest motor benefits and possible disease-modifying effects. However, subsequent larger studies, including the phase III Exenatide-PD3 trial, failed to demonstrate significant clinical benefit. Preliminary signals have been reported in multiple system atrophy, whereas evidence in Huntington's disease, essential tremor, and other movement disorders remains largely preclinical. GLP-1RAs represents a biologically plausible but as yet unproven disease-modifying strategy in movement disorders. Translational challenges, including pharmacologic heterogeneity, variability in central nervous system exposure, and clinical trial design limitations-must be addressed. Future research should focus on biomarker-guided patient selection, optimized CNS-penetrant agents, and rigorously designed clinical trials.
2026-04-20 | Subjects Affected by Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) Elevated Brain-Derived Neurotrophic Factor (BDNF) Serum Levels.
Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) are neurodegenerative disorders with marked neuronal dysfunction and damage, accompanied by the accumulation of abnormal alpha-synuclein. Identifying the proteins involved in their specific neurodegenerative processes is important to understand shared or disease-specific mechanisms of neurodegeneration. Recent investigations into these disorders have revealed intriguing alterations in the functionality of neurotrophic factors, including and predominantly the Brain-Derived Neurotrophic Factor (BDNF). Thus, the aim of this study was to investigate the BDNF serum levels in two cohorts of DLB and MSA patients and compare them to those of healthy individuals. Investigating serum BDNF concentrations in these conditions may provide insights into aspects of the underlying mechanisms of neurodegeneration. Serum BDNF concentrations were determined using commercial enzyme-linked immunosorbent assays. All serum samples were tested in duplicate, and the reported BDNF concentrations were ng/ml. The findings demonstrated a significant increase in serum BDNF levels in both DLB and MSA patients versus healthy subjects. This increase may represent a compensatory neuroprotective response to ongoing neuronal damage or a reflection of disease-related pathophysiological mechanisms involving altered BDNF regulation. These findings contribute to a growing body of evidence implicating neurotrophic fac-tor dysregulation in the pathogenesis of α-synucleinopathies. Moreover, the findings highlight BDNF as a potential therapeutic target and a candidate adjunct biomarker for diagnosis, monitoring disease activity, or treatment response. Additional experiments will clarify this causal relationship and the utility of BDNF-based interventions in modifying the disease trajectories in DLB and MSA.
cell therapies
2026-09-21 | CD8+ T cells in synucleinopathies: differential immune mechanisms in Parkinson's disease and multiple system atrophy.
Synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA), are characterized by α-synuclein aggregation and progressive neurodegeneration. Increasing evidence implicates adaptive immune mechanisms, particularly CD8+ T cells, in their pathogenesis. To summarize and compare the role of CD8+ T lymphocytes in PD and MSA, with an emphasis on disease-specific immune mechanisms. A structured narrative review of PubMed, Embase, and Scopus databases was performed, and 15 relevant studies were included. In PD, CD8+ T cells infiltrate the substantia nigra at early disease stages, often preceding overt neurodegeneration and α-synuclein deposition, and exhibit a cytotoxic phenotype characterized by granzyme and interferon-γ expression, with potential direct interactions with MHC class I-expressing neurons. Peripheral findings further support a CD8-dominant immune response with expansion of cytotoxic subsets. In contrast, MSA is associated with a relatively CD4-dominant immune profile, with increased CD4/CD8 ratios and a broader inflammatory environment, in which CD8+ T cells appear to play a more modulatory role. Across synucleinopathies, CD8+ T cells demonstrate regional CNS infiltration, phenotypic heterogeneity, and association with microglial activation. CD8+ T cells represent a heterogeneous and context-dependent component of adaptive immunity in synucleinopathies, with a predominantly cytotoxic and potentially pathogenic role in PD and a more modulatory function in MSA. These disease-specific d ifferences pr ovide in sight in to un derlying ne uroimmune me chanisms an d su pport th e po tential of CD8+ T-cell-related pathways as biomarkers and targets for tailored immunomodulatory strategies.
2026-04-06 | Safety and Efficacy of Mesenchymal Stem Cell Therapy in Multiple System Atrophy: Systematic Review.
To systematically evaluate the efficacy and safety of mesenchymal stem cell (MSC) therapy for patients with Multiple System Atrophy (MSA) by synthesising available clinical trial evidence and clarifying signals of disease modification. MSA is a rapidly progressive and fatal neurodegenerative disorder for which no disease-modifying therapies exist. MSC therapy has emerged as a potential treatment, with mechanisms centered on neuroprotection and clinical benefit through anti-inflammatory and trophic effects rather than direct cell replacement. We systematically searched PubMed, Scopus, the Cochrane Library, and Web of Science for studies on mesenchymal stem cell (MSC) therapy in adults with probable or confirmed multiple system atrophy (MSA). Eligible studies included single-arm trials or comparisons with placebo or usual care. The primary outcome was safety and tolerability, assessed by the type and severity of adverse events. Secondary outcomes included the rate of disease progression measured by UMSARS total, Part I, and Part II scores. A total of 123 participants from seven studies were included. MSCs were administered through multiple routes, and adverse events occurred in 65-70% of participants but were mostly mild and transient. No serious MSC-related toxicity was reported. Several studies suggested slower disease progression following MSC therapy. For example, in Singer et al (2019), patients receiving high-dose MSCs showed a markedly lower rate of UMSARS total score progression compared with a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004), suggesting a possible dose-dependent effect. However, treatment effects varied across studies depending on dose, administration route, and disease stage. MSC therapy shows potential for disease modification in MSA by slowing neurological deterioration. The treatment was well tolerated, supporting the need for larger, definitive trials with standardised protocols and longer follow-up to confirm clinical benefit.
2026-03-30 | Cytotoxic T cell recognition of α-synuclein drives pathogenic immune responses in multiple system atrophy.
Multiple system atrophy (MSA) is a progressive neurologic disease, known as an α-synucleinopathy. There are currently no effective disease-modifying therapies for MSA. While neuroinflammation is a hallmark of MSA, the contribution of adaptive immune mechanisms remains poorly understood. Here, we profiled peripheral and central T cell responses in patients with MSA, in comparison with Parkinson's disease (PD) and healthy control cohorts, using single-cell transcriptomics, flow cytometry, and antigen-specific functional assays. We demonstrated that peripheral T cells from MSA patients are activated and skewed toward cytotoxic and inflammatory phenotypes. Single-cell transcriptomics further revealed clonal expansion of cytotoxic CD8+ T cells expressing GZMB, GNLY, and chemokine and integrin programs associated with brain homing. We also demonstrated that both CD4+ and CD8+ T cells from MSA patients recognize α-synuclein monomers and preformed fibrils in an HLA class I/II-dependent manner, driving proliferation, clonal expansion, and acquisition of cytotoxic features. Consistent with these peripheral responses, CD8+ T cell density was increased in the parietal cortex of postmortem MSA brain tissues, along with cytotoxic (GZMB+, GZMK+) and proinflammatory (IFNγ+) CD8+ T cells. Together, these findings demonstrate that cytotoxic T cells targeting α-synuclein are engaged in MSA, suggesting that their activity may contribute to neuroinflammation and disease progression, and highlighting this immune axis as a candidate therapeutic target for further investigation.
2024-11-26 | Human Umbilical Cord Blood-Mononuclear Cell Transplantation Improves Glymphatic System Activity in Patients with Multiple System Atrophy
Motivation: Glymhatic system as a therapeutic target for multiple system atrophy (MSA) lacks imaging markers. Goal(s): Our goal was to determine changes in imaging parameters after human umbilical cord blood mononuclear cells (hUCB-MCs) transplantation. Approach: Diffusion tensor image analysis along the perivascular space (DTI-ALPS) of MSA patients were compared with healthy controls and the ALPS indices of patients were compared before and after hUCB-MCs transplantation. Results: We found that MSA patients had lower ALPS values than health controls and that ALPS values increased after treatment. Impact: Our demonstration of a detectable decline in MSA patients and an uptick after treatment utilizing ALPS metrics provides an imaging marker to monitor the glymphatic system after hUCB-MCs transplantation.
2024-09-11 | Evolving insights into erythrocytes in synucleinopathies.
Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are characterized by neuronal loss accompanied by α-synuclein (α-syn) accumulation in the brain. While research conventionally focused on brain pathology, there is growing interest in peripheral alterations. Erythrocytes, which are rich in α-syn, have emerged as a compelling site for synucleinopathies-related alterations. Erythrocyte-derived extracellular vesicles (EVs), containing pathological α-syn species, can traverse the blood-brain barrier (BBB) under certain conditions and the gastrointestinal tract, where α-syn and gut microbiota interact extensively. This review explores the accumulating evidence of erythrocyte involvement in synucleinopathies, as well as their potential in disease pathogenesis and diagnosis. Given their unique properties, erythrocytes and erythrocyte-derived EVs may also serve as an ideal therapeutic platform for treating synucleinopathies and beyond.
gene therapies
2026-04-03 | Urogenital dysfunction in neurological diseases.
Neural damage at any level of the neuraxis can lead to urogenital dysfunction, involving the lower urinary tract (LUT) and/or the sexual organs. The LUT consists of the bladder and the urethra (plus the prostate in males); LUT dysfunction can manifest as an underactive bladder, leading to urinary retention, or as an overactive bladder, leading to urinary incontinence. Manifestations of sexual dysfunction include loss of libido and dysfunction of erection, ejaculation and orgasm. In this Review, we address the physiology and innervation of the LUT and the sexual organs and discuss various aspects of urogenital dysfunction in CNS (brain and spinal cord) disorders including stroke, Alzheimer disease, white matter disease, normal-pressure hydrocephalus, Parkinson disease, dementia with Lewy bodies, multiple system atrophy, spinal cord injury, multiple sclerosis and spina bifida. We also review advances in the management of urogenital dysfunction in patients with neurological disorders.
2026-03-12 | Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.
The aggregation of the protein alpha-synuclein (αSyn) is a common feature of multiple neurodegenerative diseases collectively called synucleinopathies, for which the pathobiology is not well understood. The different phenotypic characteristics of the synucleinopathies Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) have been proposed to originate from the distinct structures adopted by αSyn in its amyloid forms. Here, using covalent labeling and limited proteolysis coupled to mass spectrometry (LiP-MS) in vitro and in situ within neuronal cells and directly in native patient brain homogenates, we show that pathogenic αSyn from distinct synucleinopathies (PD, DLB and MSA) are structurally different. Further, we found that fibril structural differences are associated with different putative fibril interactomes and neuronal responses. We discovered disease-specific ubiquitination patterns and turnover profiles for pathogenic αSyn species, detected molecular pathways responding specifically to the uptake of different αSyn fibrillar polymorphs, and identified a subset of the involved proteins as putative interactors of αSyn. In particular, components of the ubiquitin-proteasomal System (UPS), including E3 ubiquitin ligases, chaperones, and deubiquitinating proteins, showed disease/polymorph-specific putative interaction patterns, possibly accounting for different resistance of patient-derived αSyn fibrils to degradation. Genetic modulation with CRISPR-based tools showed that members of the UPS degradation pathway (three E3 ligases: UBE3A, TRIM25, HUWE1 and the AAA+ ATPase VCP) reduced αSyn inclusions, in a strain-specific manner. LiP-MS also identified sets of proteins with altered protease susceptibility in postmortem brain homogenates of PD, DLB, and MSA patients. These sets were largely disease-specific and included proteins altered in cells treated with fibrils derived from patients with the matching disease. Our findings provide insight into cellular processes involved in the accumulation and turnover of αSyn pathogenic aggregates in PD, DLB and MSA in a disease/specific manner and constitutes a resource of potential novel drug targets in these synucleinopathies.
2026-02-27 | Metabolomics of Multiple System Atrophy Patient-Derived Striatal Medium Spiny Neurons.
In multiple system atrophy (MSA), the fatal movement disorder, cell populations of the striatum and other subcortical brain regions degenerate, leading to a rapidly progressive, atypical Parkinsonian syndrome. The pathophysiology of neurons and glial cells shows misfolding, aggregation, and increased release of the protein α-synuclein. In addition, neuronal hypoexcitability, a reduction in the activity of the mitochondrial respiratory chain, and a dysregulation of the enzymes involved in the biosynthesis of coenzyme Q10 were observed in human stem-cell models. In this study, untargeted and targeted metabolome analyses were performed with MSA patient-derived GABAergic striatal medium spiny neurons focusing on the citrate cycle and mitochondrial respiratory chain. The results indicate a significant decrease in succinate and ATP as well as an imbalanced NAD+/NADH ratio of MSA cell lines compared to matched healthy controls, suggesting alterations in mitochondrial processes which may facilitate neurodegeneration.
2026-02-21 | Accuracy of clinical diagnosis in neurodegenerative diseases - a study of 455 autopsy cases.
Precision of clinical diagnosis in neurodegenerative diseases is critically important for clinical care and study recruitment. This study aimed to investigate the clinical accuracy using gold-standard neuropathological reference. Neuropathological diagnoses from the Neurobiobank München were correlated with real-world clinical diagnoses from hospitals in Germany. Accuracy metrics, including sensitivity, specificity, and area under the curve (AUC) of clinical diagnoses, were calculated. Among nine neuropathologically diagnosed neurodegenerative diseases (Alzheimer's disease, argyrophilic grain disease, corticobasal degeneration, frontotemporal lobar degeneration, Huntington's disease, Lewy body disease, motor neuron disease, multiple system atrophy, and progressive supranuclear palsy) with a total of 455 cases, clinical sensitivity varied widely (0-100%) whereas specificity was consistently high (89.5-100%). Accuracy was very good (AUC > 0.9) for Huntington's disease, motor neuron disease, and multiple system atrophy; good (AUC = 0.8-0.9) for Alzheimer's disease, dementia with Lewy bodies/Parkinson's disease, and progressive supranuclear palsy; moderate (AUC = 0.7-0.8) for frontotemporal dementia, limited (AUC = 0.51-0.7) in the n = 20 cases with corticobasal degeneration, and no discriminatory capacity (AUC = 0.5) in the n = 6 cases with argyrophilic grain disease. Clinical diagnostic accuracy of neurodegenerative diseases varies, with sensitivity as the main limiting factor. Improving diagnostic sensitivity will be essential for early and accurate patient identification, especially as disease-modifying therapies targeting causal proteinopathies become available. Achieving this will depend on the development and clinical implementation of reliable molecular biomarkers that indicate the causal proteinopathies of neurodegenerative diseases.
2026-01-17 | Association of choroid plexus volume with brain atrophy and glucose metabolism in multiple system atrophy.
The choroid plexus (CP), a component of the glymphatic system, is essential in homeostasis and producing cerebrospinal fluid. Role of CP in multiple system atrophy (MSA) remains unclear. This study aimed to investigate the implication of the CP in MSA. This retrospective cross-sectional study included 87 MSA patients who underwent the Unified MSA Rating Scale (UMSARS), brain MRI, and18F-fluorodeoxyglucose PET scan, along with 84 healthy controls (HCs). Multivariate linear regression analyses were performed to examine the associations between CP volume (CPV) and UMSARS scores, as well as the volumes and cerebral metabolism. Compared with HCs, MSA had significantly reduced CPV (1.00 ± 0.27 vs. 1.30 ± 0.26, P < 0.001). CPV showed no association with UMSARS, however, it was positively correlated with regional cerebellar volumes. Reduced CPV was associated with lower cerebral glucose metabolism in MSA-susceptible regions, consistent with the positive association between CPV and regional cerebral glucose metabolism observed in multivariate analyses. Notably, CPV positively correlated with glucose metabolism in the brainstem (β = 0.110, P = 0.003) and cerebellar white matter (β = 0.080, P = 0.004). This study suggests that CPV is positively associated with disease burden in MSA, with CPV decreasing as disease severity increases. Further research is warranted to determine whether CPV could serve as a potential biomarker for MSA.
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2026-08-05 | A single-domain antibody targets aggregation-prone region of α-synuclein to reduce synucleinopathy, rescue neurodegeneration and improve function.
Synucleinopathies are a group of neurodegenerative disorders characterized by the accumulation of aggregated α-synuclein (α-syn), including Parkinson's disease, Dementia with Lewy Bodies, and Multiple System Atrophy. These diseases are marked by locomotor and non-motor impairments, as well as mitochondrial dysfunction and the loss of dopaminergic (DA) neurons. We have developed several anti-α-syn single-domain antibodies (sdAbs) and demonstrated the diagnostic imaging potential of two of them and the acute therapeutic benefit of one in clearing α-syn in a mouse model. However, whether these sdAbs can suppress α-syn-mediated neuronal loss and locomotor impairment in vivo remains unclear. We evaluated the therapeutic potential of five anti-α-syn sdAbs to clear pathological α-syn in mouse neuronal culture and then demonstrated their in vivo efficacy in a Drosophila model of synucleinopathy. The sdAbs differed in their efficacy to lower levels of phospho-serine 129 α-syn, prevent loss of DA neurons, alleviate mitochondrial dysfunction, improve motor function, and prolong survival in synucleinopathy flies. The most effective sdAb, 2H1, has not been reported before. It binds strongly to the aggregation prone region of α-syn and robustly improves all these disease parameters. Additionally, that sdAb is associated with α-syn in the fly neurons, as shown through proximity dependent turboID biotinylation assays. The sdAb-turboID also biotinylated α-syn-associated proteins involved in synapse/vesicle trafficking pathways, pinpointing the location of their intracellular interaction. Our findings provide an insight into the therapeutic mechanism of action of these sdAbs and strongly support their clinical development.
2026-07-16 | Development of an RNA aptamer as a therapeutic agent for synucleinopathies.
The aggregation of α-synuclein (αSyn), a 140-mer protein, has been implicated in the pathogenesis of Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. KTKEGV pseudo-repeats (KRs) in the sequence of αSyn are key mediators of its prion-like propagation and neurodegeneration. Despite the availability of symptomatic treatments, no current therapy effectively delays disease progression. Here we report a 77-nucleotide RNA aptamer called 1R6, obtained through in vitro selection, that binds with high affinity and selectivity to αSyn1-95. 1R6 significantly inhibits αSyn oligomerization and β-sheet-rich fibril assembly and promotes disaggregation of preformed fibrils. Additionally, 1R6 suppresses αSyn seeding, as determined by a FRET-based biosensor-cell assay. Cellular studies reveal that 1R6 co-transfection completely prevents αSyn-induced cytotoxicity. To assess the protective effects of 1R6 in vivo, we use a Drosophila melanogaster model expressing human αSyn in neurons. Flies fed 1R6 show improved locomotor activity, reduced photoreceptor degeneration, and decreased αSyn levels in the head. Structural characterization using 1H-15N heteronuclear multiple quantum correlation nuclear magnetic resonance experiments demonstrates that 1R6 targets KR motifs, a finding further supported by in silico simulations. Our findings support further development of RNA aptamers, such as 1R6, including evaluation of efficacy, stability, delivery, and immune responses in mammalian systems, highlighting their potential as therapeutic candidates for synucleinopathies.
2026-06-19 | Sex-Dependent Effects of CSF1R-Mediated Myeloid Cell Depletion in a Mouse Model of Multiple System Atrophy.
Sex-dependent differences in neurodegenerative disorders are becoming increasingly relevant in diagnosis and development of therapeutic targets. Although multiple system atrophy (MSA), a devastating and rapidly progressing atypical parkinsonian disorder, is distributed equally among sexes, sex-specific differences have been reported regarding autonomic dysfunctions, severity of motor symptoms, and survival rate, suggesting a need for sex-specific treatment approaches. Neuroinflammation is a prominent hallmark in MSA pathology. Distinct activation patterns and increased phagocytosis of central nervous system (CNS) myeloid cells were observed, indicating a damaging role in this disease. In our previous study, we showed that colony-stimulating factor 1 receptor (CSF1R)-mediated depletion of myeloid cells in a mouse model of MSA led to a two-faced outcome, comprised of a prolonged survival and delayed onset of neurological dystonia-like symptoms, but also an aggravated motor phenotype and loss of dopaminergic neurons. Here, we re-analyzed our previous findings to study sex-specific effects in MSA in the presence and absence of CNS myeloid cells. Intriguingly, myeloid cell depletion was initially more effective in male animals. Although no sex-specific effects were detected in motor behavior, the occurrence of dystonia-like neurological symptoms was reduced, and neuronal loss was alleviated in male animals. Together, our findings provide insight into sex-specific differences of CSF1R-mediated myeloid cell depletion in MSA, emphasizing the need to study sex-specific treatment strategies in neurodegenerative disorders.
2026-05-15 | Systemic delivery of anti-sense oligonucleotide targeting α-synuclein for treatment in a mouse model of multiple system atrophy.
Multiple System Atrophy (MSA) is a rare, sporadic, age-related synucleinopathy characterized by Parkinson-like motor symptoms and ataxia. There is no therapy for MSA other than symptomatic treatment. MSA is characterized pathologically by glial cytoplasmic inclusions (GCI) of α-synuclein (αSyn) occurring in oligodendrocytes leading to loss of myelination in the brain. We recently utilized a peptide-mediated delivery method to systemically transport an anti-sense oligonucleotide (ASO) targeted to αSyn in a mouse model of MSA. We hypothesized that systemic delivery of αSyn ASO by peptide mediated delivery to a mouse model of MSA would reduce the αSyn accumulation in oligodendrocytes and reduce the overt pathology associated with MSA. Following monthly treatments of the αSyn ASO, we found increased myelination in the corpus callosum, cerebellum and brainstem. We also observed increased numbers of oligodendrocytes and reduced gliosis; however, we did not detect changes in overall αSyn in the areas of the brain we examined. Upon further analysis, we determined the peptide-mediated delivery of αSyn ASO was not taken up by oligodendrocytes. Thus, we have successfully alleviated some of the pathology associated with MSA in a mouse model; however, without direct delivery to oligodendrocytes, other approaches may need to supplement this therapy.
2026-04-28 | Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial.
Pathological aggregation and propagation of α-synuclein species drive disease progression in multiple system atrophy (MSA). We assessed the efficacy and safety of amlenetug, a monoclonal antibody targeting aggregated α‑synuclein, versus placebo in slowing clinical disease progression in people with MSA. We did a randomised, controlled, parallel-group trial (AMULET) at 18 movement disorder and autonomic dysfunction specialist sites across the USA and Japan. Patients aged 40-75 years with MSA who had motor symptom onset in the past 5 years were randomly assigned (2:1) to intravenous amlenetug or placebo every 4 weeks for 48-72 weeks in a common close design. Randomisation was performed via an interactive response system, stratified by region and blood neurofilament light chain concentration, using a block size of three. The double-blind treatment period ended when the last randomised participant had concluded the week 48 visit. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment allocation. The primary endpoint was disease progression, assessed using a Bayesian progression model of the longitudinal changes from baseline in the Unified Multiple System Atrophy Rating Scale (UMSARS) total (parts I and II) score up to week 72, in all participants who had a valid baseline assessment and at least one valid post-baseline assessment of UMSARS total score. Safety was assessed in all treated participants. This trial is registered at ClinicalTrials.gov (NCT05104476); the open-label phase of the trial is ongoing. Between Nov 16, 2021, and Oct 6, 2022, 91 unique participants were screened, of whom 64 were randomly assigned and 61 received treatment (amlenetug n=40; placebo n=21). Among treated participants, mean age was 60·8 years (SD 7·7); 32 (52%) were male and 29 (48%) female. 48 (79%) of 61 participants completed double-blind treatment (mean 56 weeks [SD 13] treatment). The Bayesian probability of 89·4% for a true slowing of clinical disease progression did not reach the predefined threshold of 97·5%, and accordingly, the primary endpoint was not met. The effect parameter of 0·81 (2·5th to 97·5th percentile 0·56 to 1·13) equates to a non-significant slowing of clinical progression by 19% (2·5th to 97·5th percentile -13 to 44) for amlenetug versus placebo. Amlenetug was generally well tolerated, with comparable rates of treatment‑emergent adverse events (n=40 [100%] with amlenetug vs n=20 [95%] with placebo) and serious treatment‑emergent adverse events (n=12 [30%] vs n=7 [33%]). The most common treatment-emergent adverse events were COVID‑19 infection (n=11 [28%] vs n=5 [24%]), back pain (n=6 [15%] vs n=2 [10%]), headache (n=5 [13%] vs n=1 [5%]), urinary tract infection (n=4 [10%] vs n=3 [14%]), peripheral oedema ([n=4] 10% vs n=1 [5%]), flushing (n=4 [10%] vs 0), and hypertension (n=4 [10%] vs 0). Two deaths occurred in each group, with only one death, in the placebo group, considered possibly treatment related. Although the trial did not meet its primary endpoint, the statistically non-significant finding of potentially slowed clinical progression, together with an acceptable safety profile, supported further evaluation in a phase 3 trial. H Lundbeck.
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Drug Discovery Landscape
18 orphan drug designations for Multiple system atrophy.
18 orphan drug designations for Multiple system atrophy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
2-[[(4-Methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazol-5-ol | small molecules | EMA | — | PharmaLex GmbH |
Exidavnemab | antibodies | EMA | BioArctic AB | |
exidavnemab | antibodies | FDA | BioArctic AB | |
human recombinant, monoclonal antibody (mAb) of the IgG1 isotype against alpha-synuclein | antibodies | FDA | Lundbeck Pharmaceuticals LLC | |
N-(4-Methyl-3-(4-(5-(4-methylisoxazol-5-yl)pyridine-3-yl)pyrimidin-2-yl)amino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide succinate | small molecules | FDA | — | ABLi Therapeutics, Inc. |
N-Acetyl-Leucine | small molecules | FDA | — | IntraBio Inc. |
Ampreloxetine | small molecules | FDA | Theravance Biopharma Ireland Limited | |
3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole | small molecules | FDA | Teva Branded Pharmaceutical Products R&D, Inc. | |
3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole | small molecules | EMA | TEVA GmbH | |
2-[[(4-Methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazol-5-ol or 5-O-desmethyl-omeprazole | small molecules | FDA | Dasher Neuroscience Inc. | |
Human IgG1 monoclonal antibody against alpha-synuclein | antibodies | EMA | H. Lundbeck A/S | |
5,7-dichloro-2-((ethylamino)methyl)-8-hydroxy-3-methylquinazolin-4(3H)-one mesilate | small molecules | EMA | Pharma Gateway AB | |
verdiperstat | small molecules | FDA | Biohaven Pharmaceuticals, Inc. | |
5,7-Dichloro-2-((ethylamino)methyl)-8-hydroxy-3-methylquinazolin-4(3H)-one mesylate | small molecules | FDA | Alterity Therapeutics, Limited | |
Ile-Ser-Ile-Thr-Glu-Ile-Lys-Gly-Val-Ile-Val-His-Arg-Ile-Glu-Thr-Ile-Leu-Phe-Lys-Lys-Lys-Lys-Glu-Met-Pro-Ser-Glu-Glu-Gly-Tyr-Gln-Asp | peptides | EMA | — | United Neuroscience Limited |
18Fluorine-N-3-Fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) Nortropane | small molecules | FDA | — | Advanced Imaging Projects, LLC |
1-(2-isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one | small molecules | EMA | Biohaven Bioscience Ireland Limited | |
Droxidopa | small molecules | EMA | H. Lundbeck A/S |
“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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