Tau protein turnover and mitochondrial stress responses

Tau是许多与年龄相关的神经退行性疾病的发病机制中的核心参与者， 阿尔茨海默病（AD）就是最好的例子。来自AD脑的Tau通过异常的翻译后 修饰（PTM），包括在特定表位的磷酸化和乙酰化的增加。的 这一提议的基本前提是，这些异常的PTM中的许多增加了tau蛋白的自结合 和毒性。虽然不溶性纤维结构的形成受到PTM的影响，但数据强烈表明 异常修饰的tau蛋白的可溶形式是神经元毒性的介质。一个关键 KNOWLEDGE GAP是这些修饰的tau物质如何在病理上影响神经元功能。此外，本发明还 导致磷酸化和乙酰化形式增加的潜在机制， AD尚未完全阐明。有人认为，病理改变形式的改变 tau蛋白的靶向自噬机制，降解可能是一个促成因素， 它们可能会损害选择性自噬过程。事实上，有数据表明， AD相关形式的tau导致碎片化、功能障碍的线粒体水平增加，这可能是 部分是由于受损的线粒体自噬，以及线粒体质量控制的其他干扰 机制等该R21提案的总体假设是AD相关的tau修饰减缓了tau 周转，损害线粒体质量控制机制，从而增加功能性较低的细胞的存在。 伴随着氧化应激和神经元功能障碍的增加， 衰老神经元表型的开始。这个项目的新奇源于它对模式生物的使用 C.线虫及其大量的遗传、转基因和基因组资源， 广泛研究AD以及其他tau蛋白病的分子基础。年轻和年长 动物将被用于描述这些病理相关的tau种类的存在如何改变这些 作为年龄的函数。该提议的目的是检验以下假设：（1）tau在 K274和K281、在T231处磷酸化的tau或两者不如野生型tau有效地转化， 线粒体自噬受损。C. elegans单拷贝转基因模型和荧光生物传感器将用于 解决这一假设，和（2）在K274和K281处乙酰化的tau，在T231处磷酸化的tau，或两者， 通过慢性线粒体应激反应加剧毒性，导致氧化应激增加。的 这些反应对神经元年龄依赖性缺陷的相对贡献将进一步使用独特的 蠕虫中的遗传资源。这些研究的影响将是提供关键的新见解， 病理性tau种类损害神经元健康和功能的机制。他们还将 为未来的研究提供基础，阐明特定修饰形式的 tau损伤神经元过程，并鉴定用于开发AD治疗剂的新靶点。

Tau is a central player in the pathogenesis of numerous age-related neurodegenerative diseases, with Alzheimer disease (AD) being the best example. Tau from AD brain is defined by aberrant posttranslational modifications (PTMs), including increases in phosphorylation and acetylation at specific epitopes. The UNDERLYING PREMISE of this proposal is that many of these aberrant PTMs increase tau self-association and toxicity. While the formation of insoluble fibrillary structures is influenced by PTMs, data strongly indicate that soluble forms of abnormally modified tau are the mediators of neuronal toxicity. A CRITICAL KNOWLEDGE GAP is how these modified tau species pathologically impact neuronal function. Additionally, the underlying mechanisms responsible for the increased presence of phosphorylated and acetylated forms in AD have not been fully elucidated. It has been suggested that alterations in how pathologically modified forms of tau are targeted to the autophagic machinery and degraded could be a contributing factor, as well as the fact that they may impair selective autophagy processes. Indeed, there is data indicating that overexpression of AD-relevant forms of tau results in increased levels of fragmented, dysfunctional mitochondria, which may be due to in part due to impaired mitophagy, as well as other perturbations of mitochondrial quality control mechanisms. The OVERALL HYPOTHESIS of this R21 proposal is that AD relevant tau modifications slow tau turnover, impair mitochondrial quality control mechanisms and thus increase the presence of less functional mitochondria with a concomitant increase in oxidative stress and neuronal dysfunction that result in an earlier onset of an aged neuron phenotype. The NOVELTY of this project stems from its use of the model organism C. elegans and its vast repertoire of genetic, transgenic and genomic resources, which has been used extensively to investigate the molecular underpinnings of AD, as well as other tauopathies. Young and older animals will be used to delineate how the presence of these pathological relevant tau species alters these processes as a function of age. The aims of this proposal are to test the hypotheses that: (1) tau acetylated at K274 and K281, tau phosphorylated at T231, or both are not as efficiently turned over as wild type tau and impair mitophagy. C. elegans single copy transgenic models and fluorescent biosensors will be used to address this hypothesis, and (2) tau acetylated at K274 and K281, tau phosphorylated at T231, or both, exacerbate toxicity through chronic mitochondrial stress responses resulting in increased oxidative stress. The relative contribution of these responses to neuronal age-dependent deficits will be further tested using unique genetic resources available in worms. The IMPACT of these studies will be to provide crucial new insights into the mechanisms by which pathological tau species compromise neuronal health and function. They will also provide the foundation for future studies delineating the mechanisms by which specifically modified forms of tau impair neuronal processes and identifying new targets for the development of therapeutics for AD.