Stroo Esther, Koopman Mandy, Nollen Ellen A A, Mata-Cabana Alejandro
European Research Institute for the Biology of Aging, University of Groningen, University Medical Center Groningen Groningen, Netherlands.
Front Neurosci. 2017 Feb 14;11:64. doi: 10.3389/fnins.2017.00064. eCollection 2017.
As the population is aging, the incidence of age-related neurodegenerative diseases, such as Alzheimer and Parkinson disease, is growing. The pathology of neurodegenerative diseases is characterized by the presence of protein aggregates of disease specific proteins in the brain of patients. Under certain conditions these disease proteins can undergo structural rearrangements resulting in misfolded proteins that can lead to the formation of aggregates with a fibrillar amyloid-like structure. Cells have different mechanisms to deal with this protein aggregation, where the molecular chaperone machinery constitutes the first line of defense against misfolded proteins. Proteins that cannot be refolded are subjected to degradation and compartmentalization processes. Amyloid formation has traditionally been described as responsible for the proteotoxicity associated with different neurodegenerative disorders. Several mechanisms have been suggested to explain such toxicity, including the sequestration of key proteins and the overload of the protein quality control system. Here, we review different aspects of the involvement of amyloid-forming proteins in disease, mechanisms of toxicity, structural features, and biological functions of amyloids, as well as the cellular mechanisms that modulate and regulate protein aggregation, including the presence of enhancers and suppressors of aggregation, and how aging impacts the functioning of these mechanisms, with special attention to the molecular chaperones.
随着人口老龄化，诸如阿尔茨海默病和帕金森病等与年龄相关的神经退行性疾病的发病率正在上升。神经退行性疾病的病理学特征是患者大脑中存在疾病特异性蛋白质的蛋白聚集体。在某些条件下，这些疾病蛋白可发生结构重排，导致蛋白质错误折叠，进而形成具有纤维状淀粉样结构的聚集体。细胞有不同的机制来应对这种蛋白质聚集，其中分子伴侣机制构成了对抗错误折叠蛋白质的第一道防线。无法重新折叠的蛋白质会经历降解和区室化过程。传统上认为淀粉样蛋白形成是与不同神经退行性疾病相关的蛋白毒性的原因。已经提出了几种机制来解释这种毒性，包括关键蛋白质的隔离和蛋白质质量控制系统的过载。在这里，我们综述了形成淀粉样蛋白的蛋白质在疾病中的不同方面、毒性机制、淀粉样蛋白的结构特征和生物学功能，以及调节和调控蛋白质聚集的细胞机制，包括聚集增强子和抑制剂的存在，以及衰老如何影响这些机制的功能，特别关注分子伴侣。
