Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) are symptomatically characterized by parkinsonism, with the latter presenting additionally a distinctive range of atypical features. Although the majority of patients with PD and APS appear to be sporadic, genetic causes of several rare monogenic disease variants were identified. The knowledge acquired from these genetic factors indicated that defects in vesicular transport pathways, endo-lysosomal dysfunction, impaired autophagy-lysosomal protein and organelle degradation pathways, α-synuclein aggregation and mitochondrial dysfunction play key roles in PD pathogenesis. Moreover, membrane dynamics are increasingly recognized as a key player in the disease pathogenesis due lipid homeostasis alterations, associated with lysosomal dysfunction, caused by mutations in several PD and APS genes. The importance of lysosomal dysfunction and lipid homeostasis is strengthened by both genetic discoveries and clinical epidemiology of the association between parkinsonism and lysosomal storage disorders (LSDs), caused by the disruption of lysosomal biogenesis or function. A synergistic coordination between vesicular trafficking, lysosomal and mitochondria defects exist whereby mutations in PD and APS genes encoding proteins primarily involved one PD pathway are frequently associated with defects in other PD pathways as a secondary effect. Moreover, accumulating clinical and genetic observations suggest more complex inheritance patters of familial PD exist, including oligogenic and polygenic inheritance of genes in the same or interconnected PD pathways, further strengthening their synergistic connection.Here, we provide a comprehensive overview of PD and APS genes with functions in vesicular transport, lysosomal and mitochondrial pathways, and highlight functional and genetic evidence of the synergistic connection between these PD associated pathways.

中文翻译：

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与帕金森病发病机制相关的囊泡运输、溶酶体和线粒体途径之间的协同联系的遗传学视角。

帕金森病（PD）和非典型帕金森综合症（APS）的症状特征是帕金森病，后者还表现出一系列独特的非典型特征。尽管大多数 PD 和 APS 患者似乎是散发性的，但几种罕见的单基因疾病变异的遗传原因已被确定。从这些遗传因素中获得的知识表明，囊泡运输途径的缺陷、内溶酶体功能障碍、自噬-溶酶体蛋白和细胞器降解途径受损、α-突触核蛋白聚集和线粒体功能障碍在PD发病机制中发挥着关键作用。此外，膜动力学越来越被认为是疾病发病机制中的关键因素，因为脂质稳态改变与溶酶体功能障碍相关，而溶酶体功能障碍是由几个 PD 和 APS 基因突变引起的。帕金森病与溶酶体贮积症 (LSD) 之间关联的遗传学发现和临床流行病学加强了溶酶体功能障碍和脂质稳态的重要性，LSD 是由溶酶体生物合成或功能破坏引起的。囊泡运输、溶酶体和线粒体缺陷之间存在协同协调，其中编码主要涉及一种 PD 途径的蛋白质的 PD 和 APS 基因的突变经常与其他 PD 途径的缺陷相关，作为次要效应。此外，不断积累的临床和遗传学观察表明，家族性PD存在更复杂的遗传模式，包括相同或相互关联的PD途径中基因的寡基因和多基因遗传，进一步加强了它们的协同联系。在此，我们对PD和APS基因进行全面概述。具有囊泡运输、溶酶体和线粒体途径的功能，并强调这些 PD 相关途径之间协同联系的功能和遗传证据。