Aging of the Nigrostriatal System: Role of DNA Repair

Summary

Principal Investigator: Fernando Cardozo-Pelaez
Abstract: The objective of this proposal is to define the role that age-dependent accumulation oxidative damage to DNA has in dictating the neuronal loss associated with aging. Specifically, this proposal aims to understand how an intrinsic factor, such as DNA repair capacity, has a major role in regulating DNA damage and how this interplay is crucial for the stability of specific neuronal populations during the normal process of aging. This information could be useful in gleaning on the mechanisms involved in neuropathologies associated with aging, such as Parkinson's disease. Specific Aim 1. To determine the status of DNA oxidation/DNA repair and stability of the nigrostriatal pathway of wild-type and mOggl knockout mice during aging. Specific Aim 2. To evaluate age-dependent effects in the antioxidant defenses of the nigrostriatal system and determine whether the lack of mOggl alters age-dependent changes in antioxidant systems. Specific Aim 3. To investigate whether lack of mOggl activity potentiates the loss of nigrostriatal DA neurons in murine MPTP-induced Parkinsonism. 129/SVJ male mice will used, the substantia nigra and caudate putamen of mice at ages 3, 12, 18, and 24 months will be analyzed for oxidative damage to DNA, DNA repair capacity, and integrity of the nigral-caudate putamen circuitry, as assessed by dopamine levels in caudate putamen and tyrosine hydroxylase neurons in substantia nigra. To determine, whether intact DNA repair is essential in maintaining normal neuronal populations during aging, similar studies will be carried out in mice lacking mOggl (glycosylase responsible for removal of oxo8dG). To identify the response that certain neuronal populations have in overcoming elevated oxidative stress, activities and levels of endogenous antioxidant system will be assessed at each age selected for the study. Wild type and knockout mice will be challenged with the neurotoxin MPTP in order to detect changes in the dopaminergic neurons susceptibility as a consequence of aging and lack of DNA repair
Funding Period: 2004-09-15 - 2008-08-31
more information: NIH RePORT

Top Publications

  1. pmc Characterization of oxidized guanosine 5'-triphosphate as a viable inhibitor of soluble guanylyl cyclase
    Celeste Bolin
    Department of Pharmaceutical Sciences, Center for Environmental Health Sciences, University of Montana, 32 Campus Drive, Missoula, MT, USA
    Free Radic Biol Med 46:828-35. 2009
  2. pmc Assessing biomarkers of oxidative stress: analysis of guanosine and oxidized guanosine nucleotide triphosphates by high performance liquid chromatography with electrochemical detection
    Celeste Bolin
    Center for Environmental Health Sciences, Department of Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 856:121-30. 2007
  3. pmc Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD
    Jinfang Wu
    Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA
    J Neurosci 28:3-9. 2008
  4. pmc Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase
    Golo Kronenberg
    Klinik und Poliklinik fur Neurologie, Center for Stroke Research Berlin, Charite Universitatsmedizin Berlin, Campus Mitte, D 10117 Berlin, Germany
    J Neurosci 28:7219-30. 2008
  5. pmc Epigenetics, oxidative stress, and Alzheimer disease
    Nasser H Zawia
    Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA
    Free Radic Biol Med 46:1241-9. 2009
  6. pmc Hydroxyl radical oxidation of guanosine 5'-triphosphate (GTP): requirement for a GTP-Cu(II) complex
    Giselle Cerchiaro
    Centro de Ciencias Naturais e Humanas, Universidade Federal do ABC, Santo Andre SP, Brazil
    Redox Rep 14:82-92. 2009

Scientific Experts

  • Nasser Zawia
  • Celeste Bolin
  • Fernando Cardozo-Pelaez
  • Giselle Cerchiaro
  • Jinfang Wu
  • Golo Kronenberg
  • Karen Gertz
  • Benjamin Winter
  • Robert W Sobol
  • Georg Juckel
  • Gerd Kempermann
  • Rainer Hellweg
  • Rudolf Jaenisch
  • Md Riyaz Basha
  • Bryan Maloney
  • Samuel H Wilson
  • Michael Ahmadi
  • Demao Chen
  • Brian Brock
  • Jean Harry
  • Heide Hörtnagl
  • Christopher A McPherson
  • Sarah Eckart
  • Deborah C Rice
  • David Cox
  • Christoph Harms
  • Shanna B Gay
  • Mustafa Balkaya
  • Heinz Linhart
  • David P Cox
  • Debomoy K Lahiri
  • Reinhard Sohr
  • Matthias Endres

Detail Information

Publications7

  1. pmc Characterization of oxidized guanosine 5'-triphosphate as a viable inhibitor of soluble guanylyl cyclase
    Celeste Bolin
    Department of Pharmaceutical Sciences, Center for Environmental Health Sciences, University of Montana, 32 Campus Drive, Missoula, MT, USA
    Free Radic Biol Med 46:828-35. 2009
    ..This suggests that oxo(8)GTP is produced by free radicals in vivo and could have significant impact on cell functions regulated by sGC activity such as synaptic plasticity in the central nervous system...
  2. pmc Assessing biomarkers of oxidative stress: analysis of guanosine and oxidized guanosine nucleotide triphosphates by high performance liquid chromatography with electrochemical detection
    Celeste Bolin
    Center for Environmental Health Sciences, Department of Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 856:121-30. 2007
    ..Validation of this method is demonstrated along with evaluation of these analytes in control and oxidizing conditions in vitro and in HEK 293T cells. Oxidation of this triphosphate pool occurred independently of oxidation to DNA...
  3. pmc Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD
    Jinfang Wu
    Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA
    J Neurosci 28:3-9. 2008
    ..These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD...
  4. pmc Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase
    Golo Kronenberg
    Klinik und Poliklinik fur Neurologie, Center for Stroke Research Berlin, Charite Universitatsmedizin Berlin, Campus Mitte, D 10117 Berlin, Germany
    J Neurosci 28:7219-30. 2008
    ..These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency...
  5. pmc Epigenetics, oxidative stress, and Alzheimer disease
    Nasser H Zawia
    Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA
    Free Radic Biol Med 46:1241-9. 2009
    ..Although the conditions leading to early life hypo- or hypermethylation of specific genes are not known, these changes can have an impact on gene expression and imprint susceptibility to oxidative DNA damage in the aged brain...
  6. pmc Hydroxyl radical oxidation of guanosine 5'-triphosphate (GTP): requirement for a GTP-Cu(II) complex
    Giselle Cerchiaro
    Centro de Ciencias Naturais e Humanas, Universidade Federal do ABC, Santo Andre SP, Brazil
    Redox Rep 14:82-92. 2009
    ..A better understanding of the chemistry involved in this oxidative modification of GTP facilitates a more comprehensive understanding of its potential physiological consequences...