ArticleActa neuropathologica2025
Widespread distribution of α-synuclein oligomers in LRRK2-related Parkinson's disease.
Article in Acta neuropathologica, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- α-Synuclein aggregation and brain atrophy in SNCA-A53T transgenic monkeys are correlated with parkinsonism.Brain : a journal of neurology · 2026Article
- Addressing the Challenges of Translating LRRK2 Biology into Disease-Modifying Therapies: The LRRK2 Investigative Therapeutics Exchange Initiative.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Co- and Multi-Pathologies in Parkinson's Disease: An International Parkinson and Movement Disorder Society Scientific Issues Committee Review.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- Pathology and Genetics in a Global Cohort of Parkinsonian Disorders.JAMA neurology · 2026Article
- Modeling Parkinson's pathology in human iPSC dopaminergic neurons uncovers key mechanisms of Lewy body formation and heterogeneity.Science advances · 2026Article
- Seeing Invisible Oligomers: Rethinking α-Synuclein Pathology Through Proximity Ligation Assay.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation.Cell reports · 2026Article
- Metabolic stress exacerbates Parkinson's disease pathology through mitochondrial dysfunction and ferroptosis.NPJ Parkinson's disease · 2026Article
- Review
- Discordance of Dopaminergic Dysfunction and Subcortical Atrophy by α-Synuclein Status in Sporadic and Genetic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- LRRK2 and GBA1 in Lewy body diseases: neuropathological subtypes at opposite ends of a spectrum?Molecular neurodegeneration · 2026Review
- Clinical correlates of a negative cerebrospinal fluid α-synuclein seed amplification assay result in Parkinson's disease.NPJ Parkinson's disease · 2026Article
- Pathology and genetics in a global cohort of Parkinsonian Disorders.medRxiv : the preprint server for health sciences · 2026Article
- Mechanistic of LRRK2-Mediated Pyroptosis Via the NLRP3/Caspase-1/GSDMD Pathway in Parkinson's Disease Progression.Inflammation · 2026Article
- Beyond Pathology: α-Synuclein Homeostasis and Three Principles to Guide Research.Movement disorders clinical practice · 2026Article
- Higher-molecular-weight a-synuclein oligomers are increased in the brain cytosol of patients with dementia with Lewy bodies.NPJ Parkinson's disease · 2026Article
- α-Synuclein in Lewy Body Diseases: Progress, Remaining Challenges and Future Perspectives.Expert reviews in molecular medicine · 2026Review
- Evolution of disease modifying therapy clinical trial design and therapeutic endpoints for Parkinson's disease.Journal of Parkinson's disease · 2026Review
- Where do PDD and DLB SYNdromes fit in neuronal alpha-SYNuclein biological frameworks?Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- LRRK2 as a Potential Disease-Modifying Target in Sporadic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Review
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Funding
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). While the clinical features of patients with LRRK2-PD resemble those of typical PD, there are significant differences in the pathological findings. The pathological hallmark of definite PD is the presence of α-synuclein (αSYN)-positive Lewy-related pathology; however, approximately half of patients with LRRK2-PD do not have Lewy-related pathology. Lewy-related pathology is a late-stage αSYN aggregation that can be visualized with hematoxylin and eosin stains or conventional immunohistochemistry (IHC). Increasing evidence has indicated that αSYN oligomers, which represent the early-stage of αSYN aggregation, may have neurotoxicity. Visualization of αSYN oligomers requires specialized staining techniques, such as αSYN-proximity ligation assay (PLA). Distribution and severity of αSYN oligomers in the brain of patients with LRRK2-PD remain unknown. In this study, we performed phosphorylated αSYN-IHC and αSYN-PLA staining on postmortem brain sections of patients with three pathogenic LRRK2 mutants: p.G2019S (n = 5), p.I2020T (n = 5), and p.R1441C (n = 4). The severity of Lewy-related pathology and αSYN oligomers was assessed semi-quantitatively in the brainstem, limbic lobe, basal ganglia, and cerebral cortex. αSYN oligomers were detected in patients with LRRK2-PD even in those without Lewy-related pathology; a negative correlation was observed between Lewy-related pathology and αSYN oligomers (r = - 0.26 [- 0.39, - 0.12]; P < 0.0001). Our findings suggest that αSYN oligomers may represent a common pathological feature of LRRK2-PD. Notably, patients harboring p.G2019S and p.I2020T had significantly higher levels of αSYN oligomers in those without Lewy-related pathology compared to those with Lewy-related pathology. These patients also had a trend toward shorter disease duration. These results imply that in LRRK2-PD, αSYN oligomers may initially accumulate in the brain but do not progress to form Lewy-related pathology. The present study suggests that targeting αSYN oligomers may be a therapeutic strategy for LRRK2-PD even if there is no Lewy-related pathology.
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