title: Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α-Synuclein.
abstract: Parkinson's disease has long been known to involve the loss of dopaminergic neurons in the substantia nigra and the coincidental appearance of Lewy bodies containing oligomerized forms of α-synuclein. The "catecholaldehyde hypothesis" posits a causal link between these two central pathologies mediated by 3,4-dihydroxyphenylacetaldehyde (DOPAL), the most toxic dopamine metabolite. Here we determine the structure of the dominant product in reactions between DOPAL and α-synuclein, a dicatechol pyrrole lysine adduct. This novel modification results from the addition of two DOPAL molecules to the Lys sidechain amine through their aldehyde moieties and the formation of a new carbon-carbon bond between their alkyl chains to generate a pyrrole ring. The product is detectable at low concentrations of DOPAL and its discovery should provide a valuable chemical basis for future studies of DOPAL-induced crosslinking of α-synuclein.
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.
authors.forename: Jon W
authors.initials: JW
authors.lastname: Werner-Allen
authors.affiliation: Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Jenna F
authors.initials: JF
authors.lastname: DuMond
authors.affiliation: Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA. rlevine@nih.gov.
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA. bax@nih.gov.
authors.forename: Ad
authors.identifier: 0000-0002-9809-5700
authors.initials: A
authors.lastname: Bax
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D003432:Cross-Linking Reagents / Q000737:chemistry; D006801:Humans; D057230:Limit of Detection; D011758:Pyrroles / Q000737:chemistry*; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D003432:Cross-Linking Reagents; D011758:Pyrroles; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; C007430:3,4-dihydroxyphenylacetaldehyde
keywords: Paal-Knorr synthesis; Parkinson's disease; amyloid disease; covalent modification; oxidative stress