Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders.

中文翻译：

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帕金森病中的 α-突触核蛋白和内溶酶体系统：关联有罪

蛋白质 α-突触核蛋白 (α-syn) 异常积累到称为路易体 (LB) 的蛋白质包涵体中是帕金森病 (PD) 和相关疾病的神经病理学标志。有趣的是，越来越多的证据表明 LB 还由其他细胞成分组成，例如细胞膜碎片和囊泡结构，这表明内溶酶体系统的功能障碍也可能在 LB 形成和神经元变性中起作用。然而，α-syn 聚集与内溶酶体系统破坏之间的联系尚未完全阐明。在这篇综述中，我们讨论了 α-syn 和内溶酶体系统之间的潜在相互作用及其对 PD 发病机制的影响。我们提出单体和聚集的 α-syn 的积累会破坏囊泡的运输、对接和回收，导致内溶酶体系统受损，特别是自噬-溶酶体降解途径。相反，关键内体/溶酶体机制基因（LRRK2、GBA、ATP13A2）中的 PD 相关突变也有助于增加 α-syn 聚集和 LB 形成。总而言之，这些观察结果表明 α-syn 和内溶酶体系统在 PD 发病机制中具有潜在的协同作用，并代表了开发针对 PD 和相关疾病的疾病缓解治疗的可行目标。