Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Center for Molecular Biology of Heidelberg University (ZMBH), and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
J Parkinsons Dis. 2020;10(2):369-382. doi: 10.3233/JPD-191790.
The pathophysiology of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and many others converge at alpha-synuclein (α-Syn) aggregation. Although it is still not entirely clear what precise biophysical processes act as triggers, cumulative evidence points towards a crucial role for protein quality control (PQC) systems in modulating α-Syn aggregation and toxicity. These encompass distinct cellular strategies that tightly balance protein production, stability, and degradation, ultimately regulating α-Syn levels. Here, we review the main aspects of α-Syn biology, focusing on the cellular PQC components that are at the heart of recognizing and disposing toxic, aggregate-prone α-Syn assemblies: molecular chaperones and the ubiquitin-proteasome system and autophagy-lysosome pathway, respectively. A deeper understanding of these basic protein homeostasis mechanisms might contribute to the development of new therapeutic strategies envisioning the prevention and/or enhanced degradation of α-Syn aggregates.
帕金森病、路易体痴呆、多系统萎缩等疾病的病理生理学都集中在α-突触核蛋白（α-Syn）聚集上。尽管确切的生物物理过程是什么仍不完全清楚，但越来越多的证据表明蛋白质质量控制（PQC）系统在调节α-Syn 聚集和毒性方面起着关键作用。这些系统包含不同的细胞策略，它们紧密平衡蛋白质的产生、稳定性和降解，最终调节α-Syn 的水平。在这里，我们回顾了α-Syn 生物学的主要方面，重点介绍了识别和处理有毒、易聚集的α-Syn 聚集物的核心细胞 PQC 成分：分子伴侣和泛素-蛋白酶体系统以及自噬-溶酶体途径。对这些基本蛋白质动态平衡机制的深入了解可能有助于开发新的治疗策略，设想预防和/或增强α-Syn 聚集物的降解。
