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<p>Mutations in leucine-rich repeat kinase 2 (<i>LRRK2</i>) are the most common cause of familial and sporadic Parkinson’s disease (PD). While the clinical features of patients with&#xa0;<i>LRRK2</i>-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&#xa0;<i>LRRK2</i>-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&#xa0;patients with <i>LRRK2</i>-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 (<i>n</i> = 5), p.I2020T (<i>n</i> = 5), and p.R1441C (<i>n</i> = 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&#xa0;<i>LRRK2</i>-PD even in those without Lewy-related pathology; a negative correlation was observed between Lewy-related pathology and αSYN oligomers (<i>r</i> = − 0.26 [− 0.39, − 0.12]; <i>P</i> &lt; 0.0001). Our findings suggest that αSYN oligomers may represent a common pathological feature of <i>LRRK2</i>-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 <i>LRRK2</i>-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 <i>LRRK2</i>-PD even if there is no Lewy-related pathology.</p>

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

  • 期刊论文

  • 发表日期：

    2025年5月2日

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  • Hiroaki Sekiya,
  • Lukas Franke,
  • Yuki Hashimoto,
  • Mariko Takata,
  • Katsuya Nishida,
  • Naonobu Futamura,
  • Kazuko Hasegawa,
  • Hisatomo Kowa,
  • Owen A. Ross,
  • Pamela J. McLean,
  • Tatsushi Toda,
  • Zbigniew K. Wszolek,
  • Dennis W. Dickson

摘要

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.