蛋白质降解功能障碍与帕金森病

Protein Degradation Pathways and Parkinson’ s Disease

蛋白质错误折叠、聚集和沉积是许多常见神经退行性疾病的发病机制，包括帕金森病（ Parkinson＇s disease， PD）。神经细胞依赖于蛋白质的质量控制系统即蛋白质的降解途径，以维持细胞内蛋白质的动态平衡。分子伴侣、泛素-蛋白酶体系统（ubiquitin-proteasome system， UPS）和自噬溶酶体途径（autophagy -lysosomal pathway， ALP）都是该系统的重要组成部分，它们均起到调节错误折叠或去除异常蛋白质的作用。越来越多的研究表明， UPS及ALP功能障碍和PD的发病机制密切相关。易聚集蛋白α-突触核蛋白（α-synuclein，α-Syn）被认为是PD最主要的致病蛋白质，破解该蛋白质的降解机制显得尤为重要。在本文中，我们具体介绍了蛋白质降解途径在PD中的作用， UPS和ALP在降解异常蛋白质过程中的不同贡献，并以α-Syn为研究对象，探讨了不同降解途径之间的相互作用。利用蛋白质降解途径中的潜在治疗靶点，可有望改善并减少PD的发生及进展。

Protein misfolding, aggregation and deposition are common disease mechanisms in many neurodegenerative diseases in -cluding Parkinson’ s disease.Neurons rely on elaborated pathways of protein quality control and removal to maintain intracellular pro -tein homeostasis.Molecular chaperones, the ubiquitin -proteasome system （UPS） and the autophagy -lysosomal pathway （ALP） are critical pathways that mediate the refolding or removal of abnormal proteins .More and more studies about this disease have shown that dysfunction of the UPS and ALP in the pathogenesis of Parkinson ’ s disease are related to disorders .Deciphering the exact mech-anism by which the different proteolytic systems contribute to the elimination of pathogenic proteins , like α-synuclein, is therefore important .This article reviews the role of protein degradation pathways in Parkinson ’ s disease and elaborate on the different contribu-tions of the UPS and the ALP to the clearance of altered proteins , and examines the interplay between different degradation pathways . The studies in this paper provide a model for the role of the UPS and ALP in the evolution and progression of α-synuclein pathology . The putative potential of using proteindegradation pathways as novel therapeutic targets in Parkinson ’ s disease is also discusses .