Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α-Synuclein

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 m...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2016-06, Vol.55 (26), p.7374-7378
Main Authors: Werner-Allen, Jon W., DuMond, Jenna F., Levine, Rodney L., Bax, Ad
Format: Article
Language:English
Subjects:
3,4-Dihydroxyphenylacetic Acid - analogs & derivatives
3,4-Dihydroxyphenylacetic Acid - chemistry
3,4-Dihydroxyphenylacetic Acid - metabolism
3,4-Dihydroxyphenylacetic Acid - toxicity
alpha-Synuclein - chemistry
amyloid disease
covalent modification
Cross-Linking Reagents - chemistry
Humans
Limit of Detection
oxidative stress
Paal-Knorr synthesis
Parkinson's disease
Pyrroles - chemistry
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Summary: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. Amyloid disease: The primary dopamine metabolite, 3,4‐dihydroxyphenylacetaldehyde, reacts with α‐synuclein Lys residues to form dicatechol pyrrole lysine adducts, which may act as the scaffold for the protein crosslinking observed in dopaminergic cells. The dicatechol pyrrole lysine adducts were characterized by NMR spectroscopy and mass spectrometry.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201600277