title: Divalent metal ions enhance DOPAL-induced oligomerization of alpha-synuclein.
abstract: Parkinson disease (PD) features profound striatal dopamine depletion and Lewy bodies containing abundant precipitated alpha-synuclein. Mechanisms linking alpha-synucleinopathy with the death of dopamine neurons remain incompletely understood. One such link may be 3,4-dihydroxyphenylacetaldehyde (DOPAL). All of the intra-neuronal metabolism of dopamine passes through DOPAL, which is toxic. DOPAL also potently oligomerizes alpha-synuclein and alpha-synuclein oligomers are thought to be pathogenic in PD. Another implicated factor in PD pathogenesis is metal ions, and alpha-synuclein contains binding sites for these ions. In this study we tested whether divalent metal ions augment DOPAL-induced oligomerization of alpha-synuclein in cell-free system and in PC12 cells conditionally over-expressing alpha-synuclein. Incubation with divalent metal ions augmented DOPAL-induced oligomerization of alpha-synuclein (Cu(2+)>Fe(2+)>Mn(2+)), whereas monovalent Cu(1+) and trivalent Fe(3+) were without effect. Other dopamine metabolites, dopamine itself, and metal ions alone or in combination with dopamine, also had no effect. Antioxidant treatment with ascorbic acid and divalent cation chelation with EDTA attenuated the augmentation by Cu(2+) of DOPAL-induced alpha-synuclein oligomerization. Incubation of PC12 cells with L-DOPA markedly increased intracellular DOPAL content and promoted alpha-synuclein dimerization. Co-incubation with Cu(2+) amplified (p=0.01), while monoamine oxidase inhibition prevented, L-DOPA-related dimerization of alpha-synuclein (p=0.01). We conclude that divalent metal ions augment DOPAL-induced oligomerization of alpha-synuclein. Drugs that interfere with this interaction might constitute a novel approach for future treatment or prevention approaches.
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive MSC-1620, Bethesda, MD 20892-1620, USA.
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive MSC-1620, Bethesda, MD 20892-1620, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sullivan
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive MSC-1620, Bethesda, MD 20892-1620, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gross
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive MSC-1620, Bethesda, MD 20892-1620, USA.
authors.forename: Adele
authors.initials: A
authors.lastname: Cooney
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive MSC-1620, Bethesda, MD 20892-1620, USA.
authors.forename: Yehonatan
authors.initials: Y
authors.lastname: Sharabi
authors.affiliation: Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive MSC-1620, Bethesda, MD 20892-1620, USA. Electronic address: goldsteind@ninds.nih.gov.
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D001205:Ascorbic Acid / Q000737:chemistry; D002413:Cations, Divalent; D002614:Chelating Agents / Q000737:chemistry; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology; D004298:Dopamine / Q000737:chemistry; D004492:Edetic Acid / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000737:chemistry*; D008345:Manganese / Q000737:chemistry*; D016716:PC12 Cells; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000737:chemistry; D066329:Protein Aggregates; D055503:Protein Multimerization; D051381:Rats; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002413:Cations, Divalent; D002614:Chelating Agents; D066329:Protein Aggregates; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; C005975:3,4-dihydroxyphenylethanol; D008345:Manganese; C007430:3,4-dihydroxyphenylacetaldehyde; D003300:Copper; D004492:Edetic Acid; D007501:Iron; D010626:Phenylethyl Alcohol; D001205:Ascorbic Acid; D004298:Dopamine
keywords: Alpha-synuclein; Copper; DOPAL; Dopamine; Oligomerization; Parkinson disease