Aging of the Nigrostriatal System: Role of DNA Repair

描述（由申请人提供）：本提案的目的是定义年龄依赖性DNA积累氧化损伤在决定与衰老相关的神经元损失中的作用。具体来说，本研究旨在了解DNA修复能力等内在因素如何在调节DNA损伤中发挥重要作用，以及这种相互作用如何在正常衰老过程中对特定神经元群的稳定性至关重要。这些信息可能有助于了解与衰老相关的神经病理机制，如帕金森病。

DESCRIPTION (provided by applicant): 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