Tau-mediated chromatin regulation and neurodegeneration

描述(申请人提供)：微管相关蛋白tau是阿尔茨海默病(AD)和其他20多种神经退行性疾病的病理标志，阿尔茨海默病(AD)是痴呆症的最常见形式，统称为tauopathies。目前还没有针对阿尔茨海默病或其他变态反应的疾病修正疗法。果蝇互变的简单遗传模型概括了这些疾病的许多关键特征，包括进行性神经变性和异常的tau磷酸化。此外，有丝分裂后神经元的氧化应激和细胞周期激活是tau诱导的人类和果蝇tau病模型神经退行性变的关键介质。将利用遗传学、生物化学和神经病理学技术来研究tau在控制染色质结构中的作用，并确定染色质变化对神经退行性变的影响。拟议的实验将确定由于tau表达而在果蝇中发生的组蛋白修饰和染色质复合体的类型。如果我们提供令人信服的证据，证明tau通过全球染色质改变来调节神经毒性，我们的工作将为包括AD在内的tau病的发病机制提供重要的见解，并将为这些疾病提供新的治疗策略。 公共卫生相关性：微管相关蛋白tau是阿尔茨海默病(AD)和其他20多种神经退行性疾病的病理标志，阿尔茨海默病(AD)是痴呆症的最常见形式，统称为tauopathies。目前还没有针对阿尔茨海默病或其他变态反应的疾病修正疗法。我们建议在果蝇阿尔茨海默病模型中研究tau诱导的染色质改变。

DESCRIPTION (provided by applicant): The microtubule-associated protein tau is a pathological hallmark of Alzheimer's disease (AD), the most frequent form of dementia, and over twenty other neurodegenerative diseases, collectively termed "tauopathies." There is currently no disease-modifying treatment available for AD or other tauopathies. The simple genetic model of tauopathy in Drosophila melanogaster recapitulates many key features of these diseases, including progressive neurodegeneration and aberrant tau phosphorylation. Furthermore, oxidative stress and cell cycle activation in post- mitotic neurons are key mediators of tau-induced neurodegeneration in humans and Drosophila models of tauopathy. Genetic, biochemical, and neuropathological techniques will be used to investigate the role of tau in the control of chromatin structure and determine the influence of chromatin changes on neurodegeneration. The proposed experiments will identify the types of histone modifications and chromatin complexes that occur due to tau expression in Drosophila. If we produce compelling evidence that tau mediates neurotoxicity through global chromatin alterations, our work will provide significant insight into the pathogenesis of tauopathies, including AD, and will suggest new therapeutic strategies for the disorders PUBLIC HEALTH RELEVANCE: The microtubule-associated protein tau is a pathological hallmark of Alzheimer's disease (AD), the most frequent form of dementia, and over twenty other neurodegenerative diseases, collectively termed "tauopathies." There is currently no disease-modifying treatment available for AD or other tauopathies. We propose to study tau-induced chromatin alterations in a Drosophila melanogaster model of AD.