Cellular oligomerization of α-synuclein is determined by the interaction of oxidized catechols with a C-terminal sequence

Joseph R. Mazzulli, Maria Armakola, Michelle Dumoulin, Ioannis Parastatidis, Harry Ischiropoulos*

*Corresponding author for this work

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

The mechanisms that govern the formation of α-synuclein (α-syn) aggregates are not well understood but are considered a central event in the pathogenesis of Parkinson's disease (PD). A critically important modulator of α-syn aggregation in vitro is dopamine and other catechols, which can prevent the formation of α-syn aggregates in cell-free and cellular model systems. Despite the profound importance of this interaction for the pathogenesis of PD, the processes by which catechols alter α-syn aggregation are unclear. Molecular and biochemical approaches were employed to evaluate the mechanism of catechol-α-syn interactions and the effect on inclusion formation. The data show that the intracellular inhibition of α-syn aggregation requires the oxidation of catechols and the specific noncovalent interaction of the oxidized catechols with residues 125YEMPS129 in the C-terminal region of the protein. Cell-free studies using novel near infrared fluorescence methodology for the detection of covalent protein-ortho-quinone adducts showed that although covalent modification of α-syn occurs, this does not affect α-syn fibril formation. In addition, oxidized catechols are unable to prevent both thermal and acid-induced protein aggregation as well as fibrils formed from a protein that lacks a YEMPS amino acid sequence, suggesting a specific effect for α-syn. These results suggest that inappropriate C-terminal cleavage of α-syn, which is known to occur in vivo in PD brain or a decline of intracellular catechol levels might affect disease progression, resulting in accelerated α-syn inclusion formation and dopaminergic neurodegeneration.

Original languageEnglish (US)
Pages (from-to)31621-31630
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number43
DOIs
StatePublished - Oct 26 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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