Dopamine and L-dopa disaggregate amyloid fibrils: implications for Parkinson's and Alzheimer's disease.
Protein deposition diseases involve the aggregation of normally soluble proteins, leading to both fibrillar and amorphous deposits. The aggregation of alpha-synuclein is associated with Parkinson's disease, and the aggregation of the Abeta peptide is associated with Alzheimer's disease. Here we show that L-dopa, dopamine, and other catecholamines dissolve fibrils of alpha-synuclein and Abeta peptide generated in vitro. The catecholamines also inhibited the fibrillation of these proteins. In addition, intraneuronal alpha-synuclein deposits formed in a mouse model were dissolved by incubation of tissue slices with L-dopa. These catecholamines are susceptible to oxidative breakdown, and we show that oxidation products are more effective than the parent compounds in inhibition. The ability to dissolve fibrils provides a new approach for studying mechanisms and consequences (e.g., the relationship between fibril formation and neurodegeneration) of protein aggregation. It is also likely to help in the development of strategies for the prevention and treatment of protein deposition diseases.
Li
Jie
J
Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA.
Zhu
Min
M
Manning-Bog
Amy B
AB
Di Monte
Donato A
DA
Fink
Anthony L
AL
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004295:Dihydroxyphenylalanine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004837:Epinephrine / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018625:Microscopy, Atomic Force; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D020836:Protein Structure, Quaternary / Q000187:drug effects; D051843:Synucleins; D051844:alpha-Synuclein
D000682:Amyloid; D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D004295:Dihydroxyphenylalanine; D004298:Dopamine; D004837:Epinephrine