Tau-mediated chromatin regulation and neurodegeneration

描述（由申请人提供）：微管相关蛋白tau是阿尔茨海默病（AD）的病理标志，阿尔茨海默病是痴呆症最常见的形式，以及20多种其他神经退行性疾病，统称为“tau病”。目前还没有针对阿尔茨海默病或其他牛头病的治疗方法。黑胃果蝇tau病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人类和果蝇tau诱导的神经退行性变的关键介质。遗传学、生物化学和神经病理学技术将用于研究tau在控制染色质结构中的作用，并确定染色质变化对神经变性的影响。提出的实验将确定组蛋白修饰和染色质复合物的类型，这些修饰和染色质复合物是由于果蝇的tau表达而发生的。如果我们能够提供令人信服的证据，证明tau通过整体染色质改变介导神经毒性，我们的工作将为包括阿尔茨海默病在内的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

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.