Oligomerization and Membrane-binding Properties of Covalent Adducts Formed by the Interaction of α-Synuclein with the Toxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL).

Abstract

Oxidative deamination of dopamine produces the highly toxic aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL), enhanced production of which is found in post-mortem brains of Parkinson disease patients. When injected into the substantia nigra of rat brains, DOPAL causes the loss of dopaminergic neurons accompanied by the accumulation of potentially toxic oligomers of the presynaptic protein α-synuclein (aS), potentially explaining the synergistic toxicity described for dopamine metabolism and aS aggregation. In this work, we demonstrate that DOPAL interacts with aS via formation of Schiff-base and Michael-addition adducts with Lys residues, in addition to causing oxidation of Met residues to Met-sulfoxide. DOPAL modification leads to the formation of small aS oligomers that may be cross-linked by DOPAL. Both monomeric and oligomeric DOPAL adducts potently inhibit the formation of mature amyloid fibrils by unmodified aS. The binding of aS to either lipid vesicles or detergent micelles, which results in a gain of α-helix structure in its N-terminal lipid-binding domain, protects the protein against DOPAL adduct formation and, consequently, inhibits DOPAL-induced aS oligomerization. Functionally, aS-DOPAL monomer exhibits a reduced affinity for small unilamellar vesicles with lipid composition similar to synaptic vesicles, in addition to diminished membrane-induced α-helical content in comparison with the unmodified protein. These results suggest that DOPAL could compromise the functionality of aS, even in the absence of protein oligomerization, by affecting the interaction of aS with lipid membranes and hence its role in the regulation of synaptic vesicle traffic in neurons.

• Authors: Cristian Follmer, Eduardo Coelho-Cerqueira, Danilo Y Yatabe-Franco, Gabriel D T Araujo, Anderson S Pinheiro, Gilberto B Domont, David Eliezer
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 46 Pg. 27660-79 (Nov 13 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26381411 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Amyloid
• Membrane Lipids
• Schiff Bases
• alpha-Synuclein
• 3,4-Dihydroxyphenylacetic Acid
• 3,4-dihydroxyphenylacetaldehyde
• Lysine
• Dopamine

Topics

• 3,4-Dihydroxyphenylacetic Acid (analogs & derivatives, chemistry, metabolism, toxicity)
• Amyloid (chemistry, metabolism)
• Animals
• Cell Membrane (chemistry)
• Dopamine (metabolism)
• Dopaminergic Neurons (drug effects, metabolism, pathology)
• Humans
• Lysine (chemistry)
• Membrane Lipids (chemistry, metabolism)
• Oxidation-Reduction
• Parkinson Disease (metabolism, pathology)
• Rats
• Schiff Bases (chemistry)
• Substantia Nigra (drug effects, metabolism, pathology)
• alpha-Synuclein (chemistry, metabolism)