Abstract

Lewy body diseases such as Parkinson disease (PD) involve intra-neuronal deposition of the protein alpha-synuclein (AS) and depletion of nigrostriatal dopamine. Interactions of AS with dopamine oxidation products may link these neurohistopathologic and neurochemical abnormalities, via two potential pathways-spontaneous oxidation of dopamine to dopamine-quinone and enzymatic oxidation of dopamine catalyzed by monoamine oxidase to form 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is then oxidized to DOPAL-quinone. We compared these two pathways in terms of the ability of dopamine and DOPAL to modify AS. DOPAL was far more potent than dopamine both in oligomerizing and forming quinone-protein adducts with ("quinonizing") AS. The DOPAL-induced protein modifications were enhanced similarly by pro-oxidation with Cu(II) or tyrosinase and inhibited similarly by anti-oxidation with N-acetylcysteine. Dopamine oxidation evoked by Cu(II) or tyrosinase did not quinonize AS. In cultured MO3.13 human oligodendrocytes DOPAL resulted in the formation of numerous intra-cellular quinoproteins that were visualized by near infrared microscopy. We conclude that of the two routes by which oxidation of dopamine modifies AS and other proteins, that via DOPAL is more prominent. The results support developing experimental therapeutic strategies that might mitigate deleterious modifications of proteins such as AS in Lewy body diseases by targeting DOPAL formation and oxidation.