CYTOSKELETAL TRANSPORT AND NEURONAL FUNCTION

细胞骨架运输和神经元功能

• 批准号: 6050778
• 负责人: LISA A FLANAGAN
• 金额: $ 8.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6050778
• 关键词: aging; animal tissue; cell motility; cytoskeletal proteins; dynein ATPase; fluorescent dye /probe; immunoelectron microscopy; intracellular transport; microtubules; neurofilament; neuronal transport; protein purification; soma; tissue /cell culture

Accumulation of neurofilaments in neuronal cell bodies is a pathologic hallmark of several neurodegenerative diseases associated with aging, including Pick's disease, corticobasal degeneration, and ALS. This abnormal accumulation may be due to defects in neurofilament slow axonal transport, the process by which cytoskeletal proteins are transported down the axon. Slow axonal transport of cytoskeletal proteins is necessary for the maintenance of the integrity and morphology of neuronal processes during adulthood. The molecular mechanisms for slow axonal transport are not yet understood. New data described in the preliminary data section of this grant show that neurofilaments are associated with microtubule motors and that neurofilaments can translocate bidirectionally along microtubules in vitro. At least part of this motility is due to the activity of cytoplasmic dynein, which has been found associated with slow axonal transport components in axons. The goal of this project is to use cell biological studies to assess whether the observed in vitro motility of neurofilaments along microtubules is related to the in vivo transport of neurofilaments down axons. The focus of these studies fits topic area 12 in the program announcement: Extracellular matrix and cytoskeleton. In particular, this proposal is relevant to age-related changes in intracellular transport mechanisms that may relate to abnormal accumulation of cytoskeletal proteins in neuronal cell bodies in neurodegenerative diseases.

神经细胞体中神经丝的积累是几种与衰老相关的神经退行性疾病的病理标志，包括匹克病、皮质基底变性和渐冻症。这种异常积累可能是由于神经丝缓慢轴突运输的缺陷，细胞骨架蛋白沿着轴突向下运输的过程。细胞骨架蛋白的缓慢轴突运输对于维持成年期神经元过程的完整性和形态是必要的。慢轴突转运的分子机制尚不清楚。本基金初步数据部分描述的新数据表明，神经丝与微管运动有关，并且神经丝可以在体外沿微管双向移位。这种运动至少部分是由于细胞质动力蛋白的活性，它被发现与轴突中缓慢的轴突运输组分有关。本项目的目的是利用细胞生物学研究来评估观察到的神经丝沿微管的体外运动是否与神经丝沿轴突的体内运输有关。这些研究的重点符合项目公告的主题区域12：细胞外基质和细胞骨架。特别是，这一建议与细胞内运输机制的年龄相关变化有关，这可能与神经退行性疾病中神经元细胞体中细胞骨架蛋白的异常积累有关。