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.
SIGNIFICANCE STATEMENT Interactions of the protein alpha-synuclein with products of dopamine oxidation in the neuronal cytoplasm may link two hallmark abnormalities of Parkinson diseaseLewy bodies (which contain abundant alpha-synuclein) and nigrostriatal dopamine depletion (which produces the characteristic movement disorder). Of two potential routes by which dopamine oxidation may alter alpha- synuclein and other proteins, that via the autotoxic catecholaldehyde 3,4- dihydroxyphenylacetaldehyde (DOPAL) is more prominent; the results support experimental therapeutic strategies targeting DOPAL formation and DOPAL-induced protein modifications.
- The American Society for Pharmacology and Experimental Therapeutics