title: 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.affiliation: From the Departments of Physical Chemistry and the Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065 follmer@iq.ufrj.br.
authors.forename: Cristian
authors.initials: C
authors.lastname: Follmer
authors.affiliation: From the Departments of Physical Chemistry and.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Coelho-Cerqueira
authors.affiliation: From the Departments of Physical Chemistry and.
authors.forename: Danilo Y
authors.initials: DY
authors.lastname: Yatabe-Franco
authors.affiliation: Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil and.
authors.forename: Gabriel D T
authors.initials: GD
authors.lastname: Araujo
authors.affiliation: Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil and.
authors.forename: Anderson S
authors.initials: AS
authors.lastname: Pinheiro
authors.affiliation: Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil and.
authors.forename: Gilberto B
authors.initials: GB
authors.lastname: Domont
authors.affiliation: the Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065 dae2005@med.cornell.edu.
authors.forename: David
authors.initials: D
authors.lastname: Eliezer
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D012545:Schiff Bases / Q000737:chemistry; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000682:Amyloid; D008563:Membrane Lipids; D012545:Schiff Bases; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; C007430:3,4-dihydroxyphenylacetaldehyde; D008239:Lysine; D004298:Dopamine
keywords: DOPAL; Parkinson disease; dopamine; oligomers; oxidative stress; protein aggregation; α-synuclein