Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA.
Cell Mol Life Sci. 2024 Sep 3;81(1):382. doi: 10.1007/s00018-024-05419-5.
In orchestrating cell signaling, facilitating plasma membrane repair, supervising protein secretion, managing waste elimination, and regulating energy consumption, lysosomes are indispensable guardians that play a crucial role in preserving intracellular homeostasis. Neurons are terminally differentiated post-mitotic cells. Neuronal function and waste elimination depend on normal lysosomal function. Converging data suggest that lysosomal dysfunction is a critical event in the etiology of Parkinson's disease (PD). Mutations in Glucosylceramidase Beta 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) confer an increased risk for the development of parkinsonism. Furthermore, lysosomal dysfunction has been observed in the affected neurons of sporadic PD (sPD) patients. Given that lysosomal hydrolases actively contribute to the breakdown of impaired organelles and misfolded proteins, any compromise in lysosomal integrity could incite abnormal accumulation of proteins, including α-synuclein, the major component of Lewy bodies in PD. Clinical observations have shown that lysosomal protein levels in cerebrospinal fluid may serve as potential biomarkers for PD diagnosis and as signs of lysosomal dysfunction. In this review, we summarize the current evidence regarding lysosomal dysfunction in PD and discuss the intimate relationship between lysosomal dysfunction and pathological α-synuclein. In addition, we discuss therapeutic strategies that target lysosomes to treat PD.
在协调细胞信号转导、促进质膜修复、监督蛋白质分泌、管理废物清除以及调节能量消耗方面，溶酶体是不可或缺的守护者，在维持细胞内稳态方面发挥着关键作用。神经元是终末分化的有丝分裂后细胞。神经元的功能和废物清除依赖于正常的溶酶体功能。汇聚的数据表明，溶酶体功能障碍是帕金森病（PD）发病机制中的一个关键事件。β-葡萄糖脑苷脂酶 1（GBA1）和富含亮氨酸重复激酶 2（LRRK2）的突变增加了帕金森病发病的风险。此外，在散发性 PD（sPD）患者的受影响神经元中观察到溶酶体功能障碍。鉴于溶酶体水解酶积极有助于受损细胞器和错误折叠蛋白质的分解，溶酶体完整性的任何损害都可能引发蛋白质的异常积累，包括α-突触核蛋白，它是 PD 中路易体的主要成分。临床观察表明，脑脊液中的溶酶体蛋白水平可能作为 PD 诊断的潜在生物标志物，以及溶酶体功能障碍的标志。在这篇综述中，我们总结了目前关于 PD 中溶酶体功能障碍的证据，并讨论了溶酶体功能障碍与病理性α-突触核蛋白之间的密切关系。此外，我们还讨论了靶向溶酶体治疗 PD 的治疗策略。
