title: alpha-synuclein aggregation: a link between mitochondrial defects and Parkinson's disease?
abstract: 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.
authors.affiliation: Parkinson's Institute, Sunnyvale, CA 94089, USA. slee@thepi.org
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011487:Protein Conformation; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein