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- Title
Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α-Synuclein.
- Authors
Werner‐Allen, Jon W.; DuMond, Jenna F.; Levine, Rodney L.; Bax, Ad
- 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.
- Subjects
DOPAMINE; PROTEIN research; MINERAL toxicity; LEWY body dementia
- Publication
Angewandte Chemie, 2016, Vol 128, Issue 26, p7500
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201600277