Abnormal Hyperphosphorylation of Tau

Tau 蛋白异常过度磷酸化

• 批准号: 8063470
• 负责人: KHALID IQBAL
• 金额: $ 29.86万
• 依托单位: INSTITUTE FOR BASIC RES IN DEV DISABIL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063470
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Behavioral; Binding; Biological Assay; Brain; Cell Culture Techniques; Cell Nucleus; Cell fusion; Cells; Cerebral cortex; Cognition; Cytoplasm; Cytoplasmic Protein; Data; Disease; Down Syndrome; Exportins; Generations; Grant; Impaired cognition; Intervention; Karyopherins; Knowledge; Lead; Length; Lesion; Maps; Mass Spectrum Analysis; Mediating; Modeling; Modification; Molecular; Mus; N-terminal; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Normal Cell; Nuclear; Nuclear Export; Nuclear Import; Nuclear Localization Signal; Nuclear Protein; Patients; Peptide Signal Sequences; Pharmaceutical Preparations; Phosphorylation; Play; Point Mutation; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; RNA-Binding Proteins; Reporting; Research Personnel; Role; SET gene; Staging; System; Tauopathies; Testing; Therapeutic Intervention; Transgenes; Transgenic Mice; Variant; abnormally phosphorylated tau; base; genetic regulatory protein; hnRNP A2; inhibitor/antagonist; mouse model; neurofibrillary tangle formation; prevent; programs; protein phosphatase-T; self assembly; tau Proteins; tau phosphorylation; tau-protein kinase; therapeutic development; therapeutic target; tool development; trafficking

DESCRIPTION (provided by applicant): The overall objective of this proposal is to understand the molecular mechanism of neurofibrillary degeneration of abnormally hyperphosphorylated tau protein and, based on this knowledge, identify specific therapeutic targets for Alzheimer disease (AD), Down syndrome and other tauopathies which are characterized by this brain lesion. The activity of protein phosphatase (PP)-2A, which regulates phosphorylation of tau, is in turn regulated partly by its inhibitor I2PP2A. In a large percentage of neurons in AD brain, I2PP2A is translocated from its primary localization in the nucleus to the cytoplasm. As PP-2A and tau are localized in the cytoplasm, the increased cytoplasmic localization of I2PP2A in AD brain explains the inhibition of PP-2A, tau hyperphosphorylation and formation of neurofibrillary tangles. We propose (1) to investigate the molecular mechanism which controls the nuclear vs. cytoplasmic localization of I2PP2A in normal neurons. The transport factors (karyopherins) that mediate the import and export of I2PP2A into and out of the nuclei, and the I2PP2A domains which interact with these factors will be identified; (2) to elucidate the cause(s) of modified neuronal I2PP2A localization in Alzheimer's disease. We will investigate the effect of the cleavage of I2PP2A, which occurs in AD brains, on the I2PP2A interaction with the transport factors. We will also investigate the effects of the interactions of I2PP2A with other soluble and fixed proteins on I2PP2A localization in normal and AD brain, and the role of I2PP2A phosphorylation; (3) to generate transgenic mice which express the N-terminal half I2PP2A (observed in the cytoplasm of neurons in the AD brain) or a control variant of this protein localized in the nuclei, under the control of an inducible expression system. The effect of these transgenes on PP-2A activity, the activities of tau kinases regulated by PP-2A and abnormal hyperphosphorylation of tau, and as well as neurodegeneration and cognitive impairment, will be studied. These studies will lead to the elucidation of the mechanism of neurofibrillary degeneration and to the identification of one or more therapeutic targets. The studies will lead also to the generation of a cellular and an animal model of tauopathies, which can be used for the development of therapeutic drugs for diseases characterized by this lesion.

描述（由申请人提供）：本提案的总体目标是了解异常过度磷酸化 tau 蛋白的神经原纤维变性的分子机制，并基于此知识确定阿尔茨海默病 (AD)、唐氏综合症和其他 tau 病的特定治疗靶点以这种脑损伤为特征。调节 tau 磷酸化的蛋白磷酸酶 (PP)-2A 的活性反过来又部分受到其抑制剂 I2PP2A 的调节。在 AD 大脑的大部分神经元中，I2PP2A 从其主要定位于细胞核易位至细胞质。由于 PP-2A 和 tau 位于细胞质中，AD 脑中 I2PP2A 细胞质定位增加解释了 PP-2A、tau 过度磷酸化和神经原纤维缠结形成的抑制。我们建议 (1) 研究控制正常神经元中 I2PP2A 核与细胞质定位的分子机制。将确定介导 I2PP2A 进出细胞核的转运因子（核转运蛋白），以及与这些因子相互作用的 I2PP2A 结构域； (2) 阐明阿尔茨海默病中神经元 I2PP2A 定位改变的原因。我们将研究 AD 大脑中发生的 I2PP2A 裂解对 I2PP2A 与转运因子相互作用的影响。我们还将研究I2PP2A与其他可溶性和固定蛋白的相互作用对I2PP2A在正常和AD脑中定位的影响，以及I2PP2A磷酸化的作用； (3)产生转基因小鼠，其在诱导表达系统的控制下表达N端半I2PP2A（在AD脑中神经元的细胞质中观察到）或定位于细胞核中的该蛋白质的对照变体。将研究这些转基因对 PP-2A 活性、PP-2A 调节的 tau 激酶活性和 tau 异常过度磷酸化以及神经变性和认知障碍的影响。这些研究将阐明神经原纤维变性的机制并确定一种或多种治疗靶点。这些研究还将产生tau蛋白病的细胞和动物模型，可用于开发针对以这种病变为特征的疾病的治疗药物。

项目成果

Regulation of microtubule-associated proteins, protein kinases and protein phosphatases during differentiation of SY5Y cells.

SY5Y 细胞分化过程中微管相关蛋白、蛋白激酶和蛋白磷酸酶的调节。

• 发表时间: 2004-10-22
• 作者: Haque, Niloufar;Gong, Cheng;Sengupta, Amitabha;Iqbal, Khalid;Grundke
• 通讯作者: Grundke

Mechanisms of tau-induced neurodegeneration.

tau 诱导的神经变性的机制。

• 发表时间: 2009-07
• 影响因子: 12.7
• 作者: Iqbal, Khalid;Liu, Fei;Gong, Cheng;Alonso, Alejandra Del C;Grundke
• 通讯作者: Grundke

Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease.

微管相关蛋白 tau 的过度磷酸化：阿尔茨海默病的一个有前途的治疗靶点。

• 发表时间: 2008
• 影响因子: 4.1
• 作者: Gong, C;Iqbal, K
• 通讯作者: Iqbal, K

Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes.

阿尔茨海默病和糖尿病中大脑胰岛素信号通路缺陷。

• 发表时间: 2011-09
• 作者: Liu, Ying;Liu, Fei;Grundke;Iqbal, Khalid;Gong, Cheng
• 通讯作者: Gong, Cheng

Differential effects of an O-GlcNAcase inhibitor on tau phosphorylation.

O-GlcNAcase 抑制剂对 tau 磷酸化的不同影响。

• 发表时间: 2012
• 影响因子: 3.7
• 作者: Yu, Yang;Zhang, Lan;Li, Xiaojing;Run, Xiaoqin;Liang, Zhihou;Li, Yi;Liu, Ying;Lee, Moon H;Grundke;Iqbal, Khalid;Vocadlo, David J;Liu, Fei;Gong, Cheng
• 通讯作者: Gong, Cheng