The accumulation and misfolding of α‐synuclein (α‐syn) represent the main pathological hallmark of PD. Overexpression of α‐syn and failure of cellular protein degradation systems play a major role in α‐syn aggregation. The discovery of PD‐associated genes related to the autophagic‐lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α‐syn accumulates, suggesting that a crosstalk between α‐syn aggregation and autophagic‐lysosomal impairment may exist. The understanding of autophagic‐lysosomal pathway dysfunctions’ role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic‐lysosomal pathway impairment and misfolded α‐syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic‐lysosomal pathway restoration as a disease‐modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society

中文翻译：

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α-突触核蛋白聚集与自噬-溶酶体功能障碍之间的恶性循环

α-突触核蛋白（α-syn）的积累和错误折叠是 PD 的主要病理标志。α-syn 的过度表达和细胞蛋白质降解系统的失败在 α-syn 聚集中起主要作用。与自噬-溶酶体途径相关的 PD 相关基因，如 VPS35、LRRK2、GBA1、SMPD1、GALC、ASAH1、SCARB2、CTSD、CTSB 和 GLA 的发现证实了细胞清除系统功能障碍参与 PD 发病机制。重要的是，溶酶体酶活性在遗传性和散发性 PD 中都会发生改变。在 α-syn 积聚的相同大脑区域中测量到溶酶体酶活性降低，这表明 α-syn 聚集和自噬-溶酶体损伤之间可能存在串扰。对自噬-溶酶体通路功能障碍在突触核蛋白病的发病机制和进展中的作用的理解为新的可能的治疗策略开辟了新的视角。本文综述了自噬-溶酶体通路受损与错误折叠的 α-syn 聚集和传播之间相互关系的证据和机制，以及最有希望的靶向自噬-溶酶体通路恢复的化合物作为 PD 治疗的疾病修饰策略. © 2019 国际帕金森和运动障碍协会 与最有前途的化合物一起靶向自噬-溶酶体途径恢复作为 PD 治疗的疾病缓解策略。© 2019 国际帕金森和运动障碍协会 与最有前途的化合物一起靶向自噬-溶酶体途径恢复作为 PD 治疗的疾病缓解策略。© 2019 国际帕金森和运动障碍协会