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蛋白在神经元体细胞树突室中的异常积累 阿尔茨海默病 (AD) 和其他 tau蛋白病是一种标志性神经病理学病变，其与神经退行性变的机制仍未知。病理性 tau 积累在很大程度上可能与 tau 的翻译后命运有关，但对于正常神经元或神经病理状态下的 tau 更新或轴突运输知之甚少。此外，tau蛋白积累的不利后果很可能包括运输的继发性损伤和蛋白酶的激活，从而导致神经变性。该提案的总体目标是通过系统分析神经元中野生型 tau 过度表达对轴突运输和可能代谢 tau 的主要蛋白水解系统的影响，提供有关 tau 翻译后行为的基本信息。这些研究将专门检验以下假设：tau 蛋白水解或轴突运输的年龄依赖性改变有助于 tau 积累，以及对 tau 积累/功能障碍的异常蛋白水解反应会促进神经退行性变。为了实现这些目标，我们建议：1）评估野生型小鼠和tau相关神经变性小鼠模型中慢速运输和快速运输（包括tau运输）机制的能力，该模型表现出与年龄相关的tau蛋白tau 病理学和神经变性发生之前和之后的积累和细胞损失； 2) 评估正常和人 tau 转基因小鼠中可能参与 tau 转换的三个主要蛋白水解系统的功能，即钙蛋白酶-钙蛋白酶抑制素、蛋白酶体和内体/溶酶体/自噬系统； 3）确认 特定蛋白水解系统在神经元细胞和病理性 tau 蛋白更新中的作用 人tau转基因小鼠体内的积累。如果时间允许，我们还将研究对 htau 小鼠施加淀粉样蛋白-b 负荷后对轴突运输和蛋白水解的影响。