CYTOSKELETAL TRANSPORT AND NEURONAL FUNCTION

神经丝在神经元细胞体中的积累是与衰老相关的几种神经退行性疾病的病理标志，包括皮克病、皮质基底节变性和ALS。 这种异常积累可能是由于神经丝慢轴突运输缺陷，细胞骨架蛋白沿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。 慢轴突运输的分子机制还不清楚。 在本授权的初步数据部分中描述的新数据表明，神经丝与微管马达相关，并且神经丝可以在体外沿沿着双向移位。 这种运动性的至少一部分是由于细胞质动力蛋白的活性，已发现其与轴突中的慢轴突运输组分相关。 这个项目的目标是使用细胞生物学研究来评估是否观察到的体外运动的神经丝沿着微管是有关在体内运输的神经丝轴突。这些研究的重点符合计划公告中的主题区域12：细胞外基质和细胞骨架。 特别是，这一建议是相关的细胞内转运机制，可能涉及到异常积累的细胞骨架蛋白在神经退行性疾病的神经元细胞体的年龄相关的变化。

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.