Department of Neuroscience, Mayo Clinic Jacksonville, College of Medicine, Jacksonville, Florida, USA.
Cold Spring Harb Perspect Med. 2012 May;2(5):a009423. doi: 10.1101/cshperspect.a009423.
Parkinson's disease (PD), like a number of neurodegenerative diseases associated with aging, is characterized by the abnormal accumulation of protein in a specific subset of neurons. Although researchers have recently elucidated the genetic causes of PD, much remains unknown about what causes increased protein deposition in the disease. Given that increased protein aggregation may result not only from an increase in production, but also from decreased protein clearance, it is imperative to investigate both possibilities as potential PD culprits. This article provides a review of the systems that regulate protein clearance, including the ubiquitin proteasome system (UPS) and the autophagy-lysosomal pathway. Literature implicating failure of these mechanisms-such as UPS dysfunction resulting from environmental toxins and mutations in α-synuclein and parkin, as well as macroautophagic pathway failure because of oxidative stress and aging-in the pathogenesis of PD is also discussed.
帕金森病（PD）与许多与衰老相关的神经退行性疾病一样，其特征是特定子集神经元中的蛋白质异常积累。尽管研究人员最近已经阐明了 PD 的遗传原因，但对于导致疾病中蛋白质沉积增加的原因仍知之甚少。鉴于蛋白质聚集的增加不仅可能是由于产量的增加，还可能是由于蛋白质清除减少，因此必须研究这两种可能性作为潜在的 PD 罪魁祸首。本文综述了调节蛋白质清除的系统，包括泛素蛋白酶体系统（UPS）和自噬溶酶体途径。还讨论了这些机制失效的文献，例如环境毒素和α-突触核蛋白和 parkin 突变导致 UPS 功能障碍，以及由于氧化应激和衰老导致巨自噬途径失效，与 PD 的发病机制有关。
