Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Nat Rev Neurosci. 2024 Jun;25(6):393-413. doi: 10.1038/s41583-024-00812-2. Epub 2024 Apr 10.
Parkinson disease (PD) is a neurodegenerative disorder marked by the preferential dysfunction and death of dopaminergic neurons in the substantia nigra. The onset and progression of PD is influenced by a diversity of genetic variants, many of which lack functional characterization. To identify the most high-yield targets for therapeutic intervention, it is important to consider the core cellular compartments and functional pathways upon which the varied forms of pathogenic dysfunction may converge. Here, we review several key PD-linked proteins and pathways, focusing on the mechanisms of their potential convergence in disease pathogenesis. These dysfunctions primarily localize to a subset of subcellular compartments, including mitochondria, lysosomes and synapses. We discuss how these pathogenic mechanisms that originate in different cellular compartments may coordinately lead to cellular dysfunction and neurodegeneration in PD.
帕金森病（PD）是一种神经退行性疾病，其特征是黑质中多巴胺能神经元的优先功能障碍和死亡。PD 的发病和进展受到多种遗传变异的影响，其中许多遗传变异缺乏功能特征。为了确定最有希望的治疗干预靶点，重要的是要考虑到各种形式的致病功能障碍可能汇聚的核心细胞区室和功能途径。在这里，我们回顾了几种与 PD 相关的关键蛋白和途径，重点讨论了它们在疾病发病机制中潜在汇聚的机制。这些功能障碍主要定位于包括线粒体、溶酶体和突触在内的亚细胞区室的一个子集。我们讨论了这些起源于不同细胞区室的致病机制如何协调导致 PD 中的细胞功能障碍和神经退行性变。
