Widespread distribution of α-synuclein oligomers in LRRK2-related Parkinson’s disease

May 2, 2025Acta neuropathologica

Common spread of harmful alpha-synuclein clumps in Parkinson's disease linked to LRRK2

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Abstract

αSYN oligomers were detected in patients with LRRK2-PD, even in those without Lewy-related pathology.

Approximately half of patients with LRRK2-PD do not exhibit Lewy-related pathology, which is typically associated with Parkinson's disease.
A negative correlation (r = -0.26) was found between Lewy-related pathology and αSYN oligomers, indicating that higher levels of oligomers are associated with less Lewy pathology.
Patients with specific LRRK2 mutations (p.G2019S and p.I2020T) showed significantly higher levels of αSYN oligomers in the absence of Lewy-related pathology compared to those with the pathology.
There is a trend suggesting that patients with higher levels of αSYN oligomers may have a shorter disease duration.
The findings indicate that αSYN oligomers could represent a common pathological feature in LRRK2-PD, independent of Lewy-related pathology.

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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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Widespread distribution of α-synuclein oligomers in LRRK2-related Parkinson’s disease

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