Aging of the Nigrostriatal System: Role of DNA Repair

描述（由申请人提供）：本提案的目的是确定年龄依赖性累积的DNA氧化损伤在决定与衰老相关的神经元损失中的作用。具体而言，该提案旨在了解内在因素（如DNA修复能力）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对正常衰老过程中特定神经元群体的稳定性至关重要。这些信息可能有助于了解与衰老相关的神经病理学机制，如帕金森病。 具体目标1。确定衰老过程中野生型和mOggl基因敲除小鼠黑质纹状体通路的DNA氧化/DNA修复状态和稳定性。 具体目标2。评估黑质纹状体系统抗氧化防御的年龄依赖性效应，并确定缺乏mOggl是否会改变抗氧化系统的年龄依赖性变化。 具体目标3。研究mOggl活性的缺乏是否会增强MPTP诱导的帕金森病小鼠黑质纹状体DA能神经元的丢失。 使用129/SVJ雄性小鼠，分析3、12、18和24月龄小鼠的黑质和尾壳核对DNA的氧化损伤、DNA修复能力和黑质-尾壳核回路的完整性，如通过尾壳核中的多巴胺水平和黑质中的酪氨酸羟化酶神经元所评估的。为了确定完整的DNA修复是否是在衰老期间维持正常神经元群体所必需的，将在缺乏mOggl（负责去除oxo 8dG的糖基化酶）的小鼠中进行类似的研究。为了确定某些神经元群体在克服升高的氧化应激中的反应，将在选择用于研究的每个年龄评估内源性抗氧化系统的活性和水平。将用神经毒素MPTP攻击野生型和基因敲除小鼠，以检测由于衰老和缺乏DNA修复而引起的多巴胺能神经元易感性的变化

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