Metal-catalyzed oxidation of alpha-synuclein: helping to define the relationship between oligomers, protofibrils, and filaments.
Oxidative stress is implicated in a number of neuro-degenerative diseases and is associated with the selective loss of dopaminergic neurons of the substantia nigra in Parkinson's disease. The role of alpha-synuclein as a potential target of intracellular oxidants has been demonstrated by the identification of posttranslational modifications of synuclein within intracellular aggregates that accumulate in Parkinson's disease brains, as well as the ability of a number of oxidative insults to induce synuclein oligomerization. The relationship between these relatively small soluble oligomers, potentially neurotoxic synuclein protofibrils, and synuclein filaments remains unclear. We have found that metal-catalyzed oxidation of alpha-synuclein inhibited formation of synuclein filaments with a concomitant accumulation of beta sheet-rich oligomers that may represent synuclein protofibrils. Similar results with a number of oxidative and enzymatic treatments suggest that the covalent association of synuclein into higher molecular mass oligomers/protofibrils represents an alternate pathway from filament formation and renders synuclein less prone to proteasomal degradation.
Cole
Nelson B
NB
Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ncole@mail.nih.gov
Murphy
Diane D
DD
Lebowitz
Jacob
J
Di Noto
Luca
L
Levine
Rodney L
RL
Nussbaum
Robert L
RL
D008841:Actin Cytoskeleton / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D007700:Kinetics; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism; D008670:Metals / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D046911:Macromolecular Substances; D008670:Metals; D009419:Nerve Tissue Proteins; D016877:Oxidants; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D007501:Iron