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.

小鼠神经元体细胞树突区室中tau的异常积聚 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，其与神经变性的机制尚不清楚。病理性tau蛋白积累很可能在很大程度上与tau蛋白的翻译后命运有关，但对正常神经元或神经病理状态下的tau蛋白周转或轴突运输知之甚少。此外，tau积累的不良后果可能包括继发性转运障碍和蛋白酶激活，导致神经变性。本提案的总体目标是通过系统分析神经元中野生型tau蛋白过度表达对轴突运输和可能代谢tau蛋白的主要蛋白水解系统的影响，提供有关tau蛋白翻译后行为的基本信息。这些研究将专门测试以下假设：tau蛋白水解或轴突转运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促进神经变性。为了实现这些目标，我们提出：1）在tau病理学和神经变性发作之前和之后，在野生型小鼠和tau相关神经变性的小鼠模型中评估慢转运和快转运（包括tau转运）的机制的能力，所述tau相关神经变性的小鼠模型表现出年龄相关的tau积累和细胞损失; 2）在正常和人tau转基因小鼠中，评估可能涉及tau转换的三个主要蛋白水解系统的功能，即钙蛋白酶-钙蛋白酶抑制蛋白、蛋白酶体和内体/溶酶体/自噬系统; 特异性蛋白水解系统在神经元细胞和病理性tau蛋白转换中的作用 在人tau转基因小鼠体内的累积。如果时间允许，我们还将研究在htau小鼠上叠加淀粉样蛋白b负荷后对轴突运输和蛋白水解的影响。