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Inhibition of α-Synuclein Aggregation by Antioxidants and Chaperones in Parkinson’s Disease

  • Jean-Christophe Rochet
  • Fang Liu
Chapter
Part of the Focus on Structural Biology book series (FOSB, volume 7)

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder involving a loss of dopaminergic neurons from the substantia nigra. A characteristic feature of the post-mortem brains of PD patients is the presence in surviving neurons of Lewy bodies, cytosolic inclusions enriched with fibrillar forms of the presynaptic protein α-synuclein. Upon prolonged incubation at physiological temperature, α-synuclein converts from a natively unfolded protein to β-sheet-rich fibrils. α-Synuclein fibrillization involves a transient buildup of ‘protofibrils’, prefibrillar oligomers that may elicit neurotoxicity by permeabilizing phospholipid membranes and/or by interfering with cellular protein clearance mechanisms. The formation of α-synuclein protofibrils is stimulated by post-translational modifications (e.g. tyrosine nitration, dopamine adduct formation, methionine oxidation) that occur readily under conditions of oxidative stress. α-Synuclein self-assembly is inhibited by the antioxidant repair enzyme methionine sulfoxide reductase A, antioxidant compounds, and various proteins with molecular chaperone activity. The upregulation of antioxidant- and chaperone-dependent mechanisms may be a reasonable therapeutic strategy for suppressing α-synuclein aggregation and toxicity in PD.

Keywords

Multiple System Atrophy Rosmarinic Acid Methionine Sulfoxide Reductase Dopaminergic Cell Death Primary Midbrain Culture 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Jean-Christophe Rochet
    • 1
  • Fang Liu
  1. 1.Department of Medicinal Chemistry and Molecular PharmacologyPurdue UniversityWest LafayetteUSA

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