Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct.
The substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily alpha-synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and alpha-synuclein fibrilization. All but one of 15 fibril inhibitors were catecholamines related to dopamine. The inhibitory activity of dopamine depended on its oxidative ligation to alpha-synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of the alpha-synuclein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of alpha-synuclein-associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies.
Conway
K A
KA
Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Rochet
J C
JC
Bieganski
R M
RM
Lansbury
P T
PT
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism; D002395:Catecholamines / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007980:Levodopa / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D011809:Quinones / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013572:Synaptic Vesicles / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D000975:Antioxidants; D001704:Biopolymers; D002395:Catecholamines; D009419:Nerve Tissue Proteins; D011809:Quinones; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D007980:Levodopa; D004298:Dopamine