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Related Experiment Videos

Oxidative modifications of alpha-synuclein.

Harry Ischiropoulos1

  • 1Stokes Research Institute, Department of Biochemistry and Biophysics, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ischirop@mail.med.upenn.edu

Annals of the New York Academy of Sciences
|July 9, 2003
PubMed
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Nitration of alpha-synuclein (alpha-syn) by reactive nitrogen species inhibits its fibril formation, leading to toxic aggregates found in neurodegenerative synucleinopathies.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Hallmark lesions in neurodegenerative synucleinopathies feature alpha-synuclein (alpha-syn) modified by tyrosine nitration and dityrosine cross-linking.
  • These modifications generate stable alpha-syn oligomers, suggesting a role for reactive nitrogen species (RNS) in disease pathogenesis.

Purpose of the Study:

  • To investigate the impact of alpha-syn nitration on its aggregation and biochemical properties.
  • To explore the formation of alpha-syn inclusions under conditions that induce nitration.

Main Methods:

  • In vitro experiments and cell transfection models using wild-type and mutant alpha-syn.
  • Analysis of alpha-syn biochemical characteristics in response to nitrating conditions.

Related Experiment Videos

Main Results:

  • Conditions inducing alpha-syn nitration also led to the formation of alpha-syn inclusions with biochemical similarities to those in human lesions.
  • Post-translational modification of alpha-syn by RNS inhibited fibril formation.
  • This modification resulted in urea- and SDS- insoluble, protease-resistant alpha-syn aggregates.

Conclusions:

  • Reactive nitrogen species play a significant role in modifying alpha-synuclein.
  • RNS-modified alpha-syn forms insoluble aggregates, potentially contributing to cellular toxicity in synucleinopathies.
  • A model is proposed where oxidants and nitrating species differentially affect alpha-syn fibrillization.