Seeking a Mechanism for the Toxicity of Oligomeric α-Synuclein

In a number of neurological diseases including Parkinson's disease (PD), alpha-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 alpha-synuclein in vivo. The toxicity of alpha-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 alpha-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic alpha-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 alpha-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of alpha-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described.