title: Seeking a mechanism for the toxicity of oligomeric α-synuclein.
abstract: In a number of neurological diseases including Parkinson's disease (PD), α-synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of α-synuclein in vivo. The toxicity of α-synuclein is popularly attributed to the formation of "toxic oligomers": a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of α-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between α-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of α-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described.
authors: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK. H.L.Roberts@bath.ac.uk.
authors: Hazel L
authors: HL
authors: Roberts
authors: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK. D.R.Brown@bath.ac.uk.
authors: David R
authors: DR
authors: Brown
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D006801:Humans; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D055503:Protein Multimerization; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein