Sekiya Hiroaki, Franke Lukas, Hashimoto Yuki, Takata Mariko, Nishida Katsuya, Futamura Naonobu, Hasegawa Kazuko, Kowa Hisatomo, Ross Owen A, McLean Pamela J, Toda Tatsushi, Wszolek Zbigniew K, Dickson Dennis W
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
Acta Neuropathol. 2025 May 2;149(1):42. doi: 10.1007/s00401-025-02872-9.
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.
富含亮氨酸重复激酶2（LRRK2）突变是家族性和散发性帕金森病（PD）最常见的病因。虽然LRRK2-PD患者的临床特征与典型PD患者相似，但病理结果存在显著差异。确诊PD的病理标志是存在α-突触核蛋白（αSYN）阳性的路易氏相关病理；然而，约一半的LRRK2-PD患者没有路易氏相关病理。路易氏相关病理是晚期αSYN聚集，可通过苏木精和伊红染色或传统免疫组织化学（IHC）观察到。越来越多的证据表明，代表αSYN聚集早期阶段的αSYN寡聚体可能具有神经毒性。αSYN寡聚体的可视化需要专门的染色技术，如αSYN邻近连接分析（PLA）。LRRK2-PD患者大脑中αSYN寡聚体的分布和严重程度尚不清楚。在本研究中，我们对三名携带致病性LRRK2突变（p.G2019S，n = 5；p.I2020T，n = 5；p.R1441C，n = 4）患者的死后脑切片进行了磷酸化αSYN-IHC和αSYN-PLA染色。在脑干、边缘叶、基底神经节和大脑皮层中对路易氏相关病理和αSYN寡聚体的严重程度进行了半定量评估。即使在没有路易氏相关病理的LRRK2-PD患者中也检测到了αSYN寡聚体；路易氏相关病理与αSYN寡聚体之间存在负相关（r = -0.26 [-0.39，-0.12]；P < 0.0001）。我们的研究结果表明，αSYN寡聚体可能代表LRRK2-PD的一种常见病理特征。值得注意的是，与伴有路易氏相关病理的患者相比，携带p.G2019S和p.I2020T且没有路易氏相关病理的患者中αSYN寡聚体水平显著更高。这些患者的病程也有缩短的趋势。这些结果意味着，在LRRK2-PD中，αSYN寡聚体可能最初在大脑中积累，但不会发展形成路易氏相关病理。本研究表明，即使没有路易氏相关病理，靶向αSYN寡聚体可能是LRRK2-PD的一种治疗策略。
