Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease.
Parkinson's disease (PD) is linked to mutations in the protein alpha-synuclein, which can exist in vitro in several aggregation states, including a natively unfolded monomer, a beta-sheet rich oligomer, or protofibril, and a stable amyloid fibril. This work reviews the current literature that is relevant to two linked questions: which of these species is pathogenic, and what is the mechanism of neurotoxicity? The amyloid fibril, fibrillar aggregates, Lewy bodies, and the alpha-synuclein monomer, which is normally expressed at high levels, are all unlikely to be pathogenic, for reasons discussed here. We therefore favor a toxic protofibril scenario, and propose that the pathogenic species is transiently populated during the process of fibrillization. Toxicity may arise from pore-like protofibrils that cause membrane permeabilization. An approach to testing this hypothesis is discussed.
Volles
Michael J
MJ
Center for Neurologic Diseases, Brigham and Women's Hospital, and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
Lansbury
Peter T
PT
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051843:Synucleins; D051844:alpha-Synuclein
D000682:Amyloid; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein