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bioRxiv · 10.1101/2024.12.18.629265

Widespread Distribution of α-Synuclein Oligomers in LRRK2-related Parkinson's Disease

Sekiya, H.·Franke, L.·Hashimoto, Y.·Takata, M.·Nishida, K.·Futamura, N.·Hasegawa, K.·Kowa, H.·Ross, O. A.·McLean, P. J.·Toda, T.·Wszolek, Z. K.·Dickson, D. W.
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Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinsons disease (PD). While the clinical features of LRRK2-PD patients resemble those of typical PD, there are significant differences in the pathological findings. The pathological hallmark of definite PD is the presence of -synuclein (SYN)-positive Lewy-related pathology; however, approximately half of LRRK2-PD cases do not have Lewy-related pathology. Lewy-related pathology is a late-stage SYN aggregation that can be visualized with hematoxylin and eosin stains or conventional immunohistochemistry (IHC). Increasing evidence has indicated that SYN oligomers, which represent the early-stage of SYN aggregation, may have neurotoxicity. Visualization of SYN oligomers requires specialized staining techniques, such as SYN-proximity ligation assay (PLA). The distribution and severity of SYN oligomers in the human brain of LRRK2-PD patients remain unknown. In this study, we performed phosphorylated SYN-IHC and SYN-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 SYN oligomers were assessed semi-quantitatively in the brainstem, limbic lobe, basal ganglia, and cerebral cortex. SYN oligomers were detected in LRRK2-PD cases even in cases without Lewy-related pathology; a negative correlation was observed between Lewy-related pathology and SYN oligomers (r=-0.26 [-0.39, -0.12]; P<0.0001). Our findings suggest that SYN oligomers may represent a common pathological feature of LRRK2-PD. Notably, patients harboring p.G2019S and p.I2020T had significantly higher levels of SYN oligomers in those without Lewy-related pathology compared to those with Lewy-related pathology. These cases also had a trend toward shorter disease duration. These results imply that in LRRK2-PD, SYN oligomers may initially accumulate in the brain but do not progress to form Lewy-related pathology. The present study suggests that targeting SYN oligomers may be a therapeutic strategy for LRRK2-PD even if there is no Lewy-related pathology.

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Sekiya, H., Franke, L., Hashimoto, Y., Takata, M., Nishida, K., Futamura, N., Hasegawa, K., Kowa, H., Ross, O. A., McLean, P. J., Toda, T., Wszolek, Z. K., Dickson, D. W.. 2024-12-20. Widespread Distribution of α-Synuclein Oligomers in LRRK2-related Parkinson's Disease. https://doi.org/10.1101/2024.12.18.629265

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