PHOSPHORYLATION AND SPATIAL LOCALIZATION OF TAU PROTEIN

Tau蛋白是一种神经元微管相关蛋白，可促进 微管组装及其在轴突发育中的作用。另外， 异常磷酸化的tau是神经纤维的一个组成部分 缠结，从而可能有助于阿尔茨海默病的发病机制。 虽然人们对微管中tau的结构和功能知之甚少 集合，控制tau空间定位的机制，以及 调节tau的磷酸化，因此它的活性很差。 明白了。申请人已经确定，在转基因的神经元中 细胞，tau的氨基末端定位在细胞膜上， 对轴突生长产生显性的负面影响。她假设 Tau介导微管-膜相互作用，这是 神经元性发育。在这里，她提议检验这一假设。 Tau与膜结合的分子基础将是 阐明这种联系及其在神经元中的意义 差异化将被确定。确定…的分子基础 牛磺酸与膜的关系，申请者将1)识别 与膜结合的tau氨基末端的面积，2)确定 牛磺酸与纯化牛磺酸结合的生化特征 膜，以及3)确定膜的相互作用的成分(S 与tau使用免疫共沉淀。调查……的作用 膜相关tau在神经元分化过程中，她将1) 未转染分化神经元中膜相关tau蛋白的检测 细胞和原代培养的神经元中，2)研究 膜相关tau结构域在神经元中的过度表达 差异化。 这些研究将为了解tau的氨基功能提供新的见解 末端和tau在细胞外信号转导中的作用 到细胞骨架。

Tau protein is a neuronal microtubule associated protein that promotes microtubule assembly and functions in axonal development. Additionally, abnormally phosphorylated tau is an integral component of neurofibrillary tangles and thus may contribute to Alzheimer's disease pathogenesis. While much is known about the structure and function of tau in microtubule assembly, the mechanisms that govern tau's spatial localization and that regulate tau phosphorylation, and thus its activity, are poorly understood. The applicant has determined that in transfected neuronal cells, the amino terminal of tau localizes to the cell membrane and creates a dominant negative effect on neurite outgrowth. She hypothesizes that tau mediates microtubule-membrane interactions that are required for neuritic development. Here she proposes to test this hypothesis. The molecular basis for tau's association with the membrane will be elucidated and the significance of this association in neuronal differentiation will be determined. To determine the molecular basis of tau's association with the membrane, the applicant will 1) identify the area of the amino terminus of tau that binds to the membrane, 2) determine the biochemical characteristics of the binding between tau and purified membrane, and 3) identify the component(s) of the membrane that interact with tau using co-immunoprecipitation. To investigate the role of membrane associated tau during neuronal differentiation, she will 1) examine membrane associated tau in non-transfected differentiated neuronal cells and in primary cultured neurons and 2) investigate the effect of over expressing the membrane associated tau domain during neuronal differentiation. These studies will provide new insights into the function of tau's amino terminus and into tau's role in the transduction of extracellular signals to the cytoskeleton.