In VIvo Proteolysis and Axonal Transport in Tauopathy

Tau 病中的体内蛋白水解和轴突运输

• 批准号: 6966710
• 负责人: RALPH A. NIXON
• 金额: $ 27.67万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966710
• 关键词: age difference; amyloid proteins; autophagy; calpain; genetically modified animals; histopathology; laboratory mouse; lysosomes; neural degeneration; neuronal transport; neuropathology; posttranslational modifications; proteasome; protein localization; protein transport; proteolysis; tau proteins

The abnormal accumulation of tau within the somatic dendritic compartment of neurons in Alzheimer's disease (AD) and other tauopathies is a hallmark neuropathologic lesion linked by still unknown mechanisms to neurodegeneration. Pathologic tau accumulation is likely to be related, in large part, to tau's posttranslational fate, but remarkably little is known about tau turnover or axonal transport in either normal neurons or in neuropathologic states. Moreover, adverse consequences of tau accumulation may well include secondary impairments of transport and activation of proteases leading to neurodegeneration. The overall goal of this proposal will be to provide fundamental information about the posttranslational behavior of tau by systematically analyzing the consequences of wild-type tau overexpression in neurons on axonal transport and on major proteolytic systems that may metabolize tau. These studies will specifically test the hypotheses that age-dependent alterations of tau proteolysis or axonal transport contribute to tau accumulation and that abnormal, proteolytic responses to tau accumulation/dysfunction promote neurodegeneration. To achieve these goals, we propose to: 1) evaluate the competency of the mechanisms for slow transport and fast transport, including tau transport, in wild-type mice and in a mouse model of tau-related neurodegeneration, which exhibits age-related tau accumulation and cell loss, before and after the onset of tau pathology and neurodegeneration; 2) assess the function of three major proteolytic systems potentially involved in tau turnover, the calpain-calpastatin, proteasome, and endosomal/lysosomal/autophagic systems, in normal and human tau transgenic mice; 3) confirm the role of specific proteolytic systems in tau turnover in neuronal cells and in pathologic tau accumulation in human tau transgenic mice in vivo. As time permits, we will also investigate effects on axonal transport and proteolysis after superimposing an amyloid-b burden on htau mice.

Tau在神经元中的体细胞树突中的异常积累 阿尔茨海默氏病（AD）和其他tauopathies是一种标志性的神经病变病变，其仍然未知机制与神经变性相关。病理学的积累很大程度上可能与Tau的翻译后命运有关，但对于正常神经元或神经病理状态中的TAU更新或轴突运输知之甚少。此外，tau积累的不利后果很可能包括转运和激活导致神经变性的次要损害。该提案的总体目标是通过系统地分析神经元对轴突运输和可能代谢Tau的主要蛋白水解系统的野生型Tau过表达的后果来提供有关TAU翻译后行为的基本信息。这些研究将特异性检验的假设，即tau蛋白水解或轴突转运的年龄依赖性改变有助于tau积累，并且对TAU积累/功能障碍的异常，蛋白水解反应促进神经变性。为了实现这些目标，我们建议：1）评估缓慢运输和快速运输机制的能力，包括tau运输，在野生型小鼠中以及与TAU相关的神经变性的鼠标模型中，该模型表现出与年龄相关的TAU累积和细胞损失，在TAU病理病理和神经变性剂的开始之前和之后； 2）评估可能参与TAU周转的三个主要蛋白水解系统的功能，在正常和人tau转基因小鼠中，钙蛋白酶 - 卡泊蛋​​白，蛋白酶体和内体/溶酶体/自噬系统的功能； 3）确认 特定蛋白水解系统在神经元细胞和病理TAU中的TAU周转率中的作用 人体内tau转基因小鼠的积累。在时间允许的情况下，我们还将研究对HTAU小鼠叠加淀粉样蛋白B负担后对轴突运输和蛋白水解的影响。