Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson's syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies.

中文翻译：

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帕金森综合症的遗传学和发病机制


帕金森病 (PD) 在临床、病理和遗传上具有异质性，难以转化为单一的、内聚性的疾病。相反，每个受影响的个体都会患上一种几乎独特的帕金森综合症。临床表现包括可变的运动和非运动特征，并且与其他神经退行性疾病有无数的重叠。尽管最常见的特征是整个中枢和周围神经系统的 α-突触核蛋白病理学，但其分布各不相同，并且其他病理学通常会改变 PD 或引发类似的表现。几乎所有 PD 都受到遗传影响。已鉴定出 100 多个基因或遗传位点，大多数病例可能是由许多常见和罕见的遗传变异之间的相互作用引起的。尽管其结构复杂，但实验遗传解剖的见解结合起来揭示了统一的生物学主题，包括突触、溶酶体、线粒体和免疫介导的发病机制。对帕金森综合症的新认识，加上生物标志物和靶向治疗的进步，预示着精准医疗策略的成功。