Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism.
Two mutations in the protein alpha-synuclein (A30P and A53T) are linked to an autosomal dominant form of Parkinson's disease. Both mutations accelerate the formation of prefibrillar oligomers (protofibrils) in vitro, but the mechanism by which they promote toxicity is unknown. Protofibrils of wild-type alpha-synuclein bind and permeabilize acidic phospholipid vesicles. This study examines the relative membrane permeabilizing activities of the wild type, mutant, and mouse variants of protofibrillar alpha-synuclein and the mechanism of membrane permeabilization. Protofibrillar A30P, A53T, and mouse variants were each found to have greater permeabilizing activities per mole than the wild-type protein. The leakage of vesicular contents induced by protofibrillar alpha-synuclein exhibits a strong preference for low-molecular mass molecules, suggesting a pore-like mechanism for permeabilization. Under conditions in which the vesicular membrane is less stable (lack of calcium as a phospholipid counterion), protofibril permeabilization is less size-selective and monomeric alpha-synuclein can permeabilize via a detergent-like mechanism. We conclude that the pathogenesis of Parkinson's disease may involve membrane permeabilization by protofibrillar alpha-synuclein, the extent of which will be strongly dependent on the in vivo conditions.
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
D019943:Amino Acid Substitution; D000818:Animals; D002463:Cell Membrane Permeability / Q000235:genetics / Q000502:physiology*; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein