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

55 Citations (Scopus)

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

Fingerprint

Synucleins
Catechols
Oligomerization
Agglomeration
Parkinson Disease
Proteins
Modulators
Disease Progression
Amino Acid Sequence
Dopamine
Brain
Hot Temperature
Fluorescence
Infrared radiation
Amino Acids
Oxidation
Acids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Mazzulli, Joseph R. ; Armakola, Maria ; Dumoulin, Michelle ; Parastatidis, Ioannis ; Ischiropoulos, Harry. / Cellular oligomerization of α-synuclein is determined by the interaction of oxidized catechols with a C-terminal sequence. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 43. pp. 31621-31630.
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Cellular oligomerization of α-synuclein is determined by the interaction of oxidized catechols with a C-terminal sequence. / Mazzulli, Joseph R.; Armakola, Maria; Dumoulin, Michelle; Parastatidis, Ioannis; Ischiropoulos, Harry.

In: Journal of Biological Chemistry, Vol. 282, No. 43, 26.10.2007, p. 31621-31630.

Research output: Contribution to journalArticle

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