Lee Seung-Jae
Parkinson's Institute, Sunnyvale, CA 94089, USA.
Antioxid Redox Signal. 2003 Jun;5(3):337-48. doi: 10.1089/152308603322110904.
Protein aggregation is a shared feature of many human neurodegenerative diseases and appears to be an inevitable consequence of excessive accumulation of misfolded proteins. Recent studies suggest that accumulation of fibrillar alpha-synuclein aggregates is associated with Parkinson's disease and other Lewy body diseases. Furthermore, the missense mutations in alpha-synuclein that are responsible for some early-onset familial types of the disease promote the aggregation process of this protein. Therefore, the mechanism underlying the cellular alpha-synuclein aggregation is of great importance in understanding the pathogenic process of these diseases. This review summarizes recent advances in our understanding of the mechanisms underlying alpha-synuclein aggregation and how the mitochondrial dysfunction plays a role in this process. Protein misfolding and aggregation in vivo can be suppressed and promoted by several factors, such as molecular chaperones, protein degradation systems, and free radicals. Many of these factors are under the control of normal mitochondrial function, prompting the speculation that mitochondrial dysfunction might cause the accumulation of protein aggregates. Recent studies indeed show that mitochondrial defects can lead to the aggregation of alpha-synuclein. In addition, potentially toxic effects of alpha-synuclein have been linked to the aggregated forms rather than the monomers, both in vitro and in cultured cells. Therefore, it is postulated that aggregation of alpha-synuclein might be one of many possible links that connect mitochondrial dysfunction to neurodegeneration.
蛋白质聚集是许多人类神经退行性疾病的共同特征，似乎是错误折叠蛋白质过度积累的必然结果。最近的研究表明，纤维状α-突触核蛋白聚集体的积累与帕金森病和其他路易体病有关。此外，导致某些早发性家族性疾病类型的α-突触核蛋白错义突变促进了该蛋白的聚集过程。因此，细胞内α-突触核蛋白聚集的机制对于理解这些疾病的致病过程至关重要。本综述总结了我们对α-突触核蛋白聚集机制以及线粒体功能障碍在此过程中如何发挥作用的最新认识进展。体内蛋白质错误折叠和聚集可受到多种因素的抑制和促进，如分子伴侣、蛋白质降解系统和自由基。这些因素中的许多都受正常线粒体功能的控制，这促使人们推测线粒体功能障碍可能导致蛋白质聚集体的积累。最近的研究确实表明，线粒体缺陷可导致α-突触核蛋白的聚集。此外，在体外和培养细胞中，α-突触核蛋白的潜在毒性作用都与聚集形式而非单体有关。因此，据推测α-突触核蛋白的聚集可能是将线粒体功能障碍与神经退行性变联系起来的众多可能联系之一。
