Dopamine quinones interact with alpha-synuclein to form unstructured adducts.
alpha-Synuclein (alphasyn) fibril formation is considered a central event in the pathogenesis of Parkinson's disease (PD). In recent years, it has been proposed that prefibrillar annular oligomeric beta-sheet-rich species, called protofibrils, rather than fibrils themselves, may be the neurotoxic species. The oxidation products of dopamine (DAQ) can inhibit alphasyn fibril formation supporting the idea that DAQ might stabilize alphasyn protofibrils. In the present work, through different biochemical and biophysical techniques, we isolated and structurally characterized alphasyn/DAQ adducts. Contrary to protofibrils, we demonstrated that alphasyn/DAQ adducts retain an unfolded conformation. We then investigated the nature of the modifications induced on alphasyn by DAQ. Our results indicate that only a small fraction of alphasyn interacts with DAQ in a covalent way, so that non-covalent interaction appears to be the major modification induced by DAQ on alphasyn.
Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy.
Marco
M
Bisaglia
Laura
L
Tosatto
Francesca
F
Munari
Isabella
I
Tessari
Patrizia Polverino
PP
de Laureto
Stefano
S
Mammi
Luigi
L
Bubacco
D004298:Dopamine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism*; D011809:Quinones / Q000737:chemistry* / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
D011809:Quinones; D051844:alpha-Synuclein; D004298:Dopamine