Oxidative modification of brain proteins in pesticide intoxication

Summary

Principal Investigator: PIER MASTROBERARDINO
Abstract: DESCRIPTION (provided by applicant) Exposure to pesticides has been associated with oxidative stress and Parkinson's disease. Although different pesticides produce a common phenotype, the initial pathways of intoxication are specific for the individual environmental pathogen. Defining these initial pathways will help us to develop specific biomarkers and, hopefully, effective therapies. Here the investigators hypothesize that oxidation of thiols in proteins is an early event in pesticide intoxication and that individual pesticides will specifically affect different proteins, depending on their site of action. The specific aims are designed to identify those proteins that get oxidized following the administration of two different pesticides, rotenone or paraquat, and to validate their potential use as biomarkers in antioxidant therapy. The methods are based on innovative mass spectrometry and fluorescent confocal microscopy techniques. The candidate is a postdoctoral fellow in the Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh, under the supervision of Dr. Tim Greenamyre. He received his Ph.D. at the University of Rome, Italy, developing a strong background in biochemistry, molecular biology and mass spectrometry applied to neurodegenerative disorders. In 2003, the candidate moved to the U.S. to join Greenamyre's laboratory and facilitate his career development in an outstanding scientific environment. The long-term goal of the candidate is to become an established leader in the field of oxidative stress and neurodegenerative disorders, and to provide substantive scientific and social contributions to issues related to public health. The K99/R00 application provides the training requirements necessary to achieve the candidate's ambitions, improving his technical skills, complementing his basic research education with crucial clinical correlations and initiating his career as independent researcher. The University of Pittsburgh constitutes the ideal environment to develop as an independent scientist, and it ranks among the top in the nation for NIH research support. University core facilities provide state-of-the-art instrumentation and expertise, and the PIND, where the candidate will be based, is designed to be a very collaborative structure, encouraging interactions between established scientists and excellent clinicians. Exposure to very low doses of pesticides for long periods can generate disorders of the nervous system. This form of intoxication represents an under-appreciated threat to public health, in part because clinical manifestations appear long after the exposure. At that point, when medical diagnosis is possible, neuronal damage is already at advanced stages. The goal of this proposal is to find biomarkers to monitor the progression of intoxication before symptoms appear, in order to develop therapies that can be administrated at earlier stages.
Funding Period: 2009-08-15 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. pmc A FRET-based method to study protein thiol oxidation in histological preparations
    Pier G Mastroberardino
    Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Free Radic Biol Med 45:971-81. 2008
  2. pmc A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease
    Pier Giorgio Mastroberardino
    Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA
    Neurobiol Dis 34:417-31. 2009
  3. pmc Type 2 transglutaminase in Huntington's disease: a double-edged sword with clinical potential
    P G Mastroberardino
    Department of Genetics, Erasmus MC, Rotterdam, The Netherlands
    J Intern Med 268:419-31. 2010
  4. ncbi Pilocapine alters NMDA receptor expression and function in hippocampal neurons: NADPH oxidase and ERK1/2 mechanisms
    Roberto Di Maio
    Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA
    Neurobiol Dis 42:482-95. 2011

Scientific Experts

Detail Information

Publications4

  1. pmc A FRET-based method to study protein thiol oxidation in histological preparations
    Pier G Mastroberardino
    Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Free Radic Biol Med 45:971-81. 2008
    ..In summary, this technique provides a new, powerful tool for providing further understanding of oxidative imbalance, a phenomenon common to many diseases...
  2. pmc A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease
    Pier Giorgio Mastroberardino
    Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA
    Neurobiol Dis 34:417-31. 2009
    ..Thus, we have discovered a novel mitochondrial iron transport system that goes awry in PD, and which may provide a new target for therapeutic intervention...
  3. pmc Type 2 transglutaminase in Huntington's disease: a double-edged sword with clinical potential
    P G Mastroberardino
    Department of Genetics, Erasmus MC, Rotterdam, The Netherlands
    J Intern Med 268:419-31. 2010
    ..In this review we will discuss the relevance of TG2 to the pathogenesis of HD, in an effort to define novel therapeutic avenues...
  4. ncbi Pilocapine alters NMDA receptor expression and function in hippocampal neurons: NADPH oxidase and ERK1/2 mechanisms
    Roberto Di Maio
    Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA
    Neurobiol Dis 42:482-95. 2011
    ....