Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy.
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, 20122 Milan, Italy.
Int J Mol Sci. 2023 Mar 28;24(7):6338. doi: 10.3390/ijms24076338.
Parkinson's disease (PD) is the second most common neurodegenerative disorder in the aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD has been related to many dysfunctional cellular mechanisms, however, most of its monogenic forms are caused by pathogenic variants in genes involved in endolysosomal function (, , , and ) and synaptic vesicle trafficking (, , , and ). Moreover, an extensive search for PD risk variants revealed strong risk variants in several lysosomal genes (e.g., , , , and ) highlighting the key role of lysosomal dysfunction in PD pathogenesis. Furthermore, large genetic studies revealed that PD status is associated with the overall "lysosomal genetic burden", namely the cumulative effect of strong and weak risk variants affecting lysosomal genes. In this context, understanding the complex mechanisms of impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons of PD patients is a fundamental step to identifying precise therapeutic targets and developing effective drugs to modify the neurodegenerative process in PD.
帕金森病（PD）是老龄化人口中第二常见的神经退行性疾病，迄今为止尚无批准的疾病修饰疗法。PD 的发病机制与许多功能失调的细胞机制有关，但大多数其单基因形式是由参与内溶酶体功能（ ， ， ，和 ）和突触囊泡转运（ ， ， ，和 ）的基因中的致病性变异引起的。此外，对 PD 风险变异的广泛搜索揭示了几个溶酶体基因中的强风险变异（例如 ， ， ，和 ），突出了溶酶体功能障碍在 PD 发病机制中的关键作用。此外，大型遗传研究表明，PD 状态与整体“溶酶体遗传负担”相关，即影响溶酶体基因的强和弱风险变异的累积效应。在这种情况下，了解 PD 患者多巴胺能神经元中囊泡转运受损和内溶酶体功能障碍的复杂机制是确定精确治疗靶点和开发有效药物以改变 PD 神经退行性过程的基本步骤。
