Exploring the role of methionine residues on the oligomerization and neurotoxic properties of DOPAL-modified α-synuclein. Academic Article uri icon

Overview

abstract

  • The dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is believed to play a central role in Parkinson's disease neurodegeneration by stabilizing potentially toxic oligomers of the presynaptic protein α-Synuclein (aSyn). Besides the formation of covalent DOPAL-Lys adducts, DOPAL promotes the oxidation of Met residues of aSyn, which is also a common oxidative post-translational modification found in the protein in vivo. Herein we set out to address the role of Met residues on the oligomerization and neurotoxic properties of DOPAL-modified aSyn. Our data indicate that DOPAL promotes the formation of two distinct types of aSyn oligomers: large and small (dimer and trimers) oligomers, which seem to be generated by independent mechanisms and cannot be interconverted by using denaturing agents. Interestingly, H2O2-treated aSyn monomer, which exhibits all-four Met residues oxidized to Met-sulfoxide, exhibited a reduced ability to form large oligomers upon treatment with DOPAL, with no effect on the population of small oligomers. In this context, triple Met-Val mutant M5V/M116V/M127V exhibited an increased population of large aSyn-DOPAL oligomers in comparison with the wild-type protein. Interestingly, the stabilization of large rather than small oligomers seems to be associated with an enhanced toxicity of DOPAL-aSyn adducts. Collectively, these findings indicate that Met residues may play an important role in modulating both the oligomerization and the neurotoxic properties of DOPAL-derived aSyn species.

publication date

  • September 22, 2018

Research

keywords

  • 3,4-Dihydroxyphenylacetic Acid
  • Methionine
  • Neurons
  • Protein Multimerization
  • alpha-Synuclein

Identity

PubMed Central ID

  • PMC6293985

Scopus Document Identifier

  • 85053722821

Digital Object Identifier (DOI)

  • 10.1016/j.bbrc.2018.09.111

PubMed ID

  • 30249394

Additional Document Info

volume

  • 505

issue

  • 1