CYTOSKELETAL TRANSPORT AND NEURONAL FUNCTION

神经元体中神经丝的堆积是几种与衰老相关的神经退行性疾病的病理特征，包括皮克氏病、皮质基底膜退行性变和ALS。这种异常堆积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。在成年期，细胞骨架蛋白的缓慢轴突运输对于维持神经元突起的完整性和形态是必要的。轴突运输缓慢的分子机制尚不清楚。这项资助的初步数据部分描述的新数据表明，神经丝与微管马达有关，在体外神经丝可以沿着微管双向转移。这种运动至少有一部分是由于胞浆动力蛋白的活动，它被发现与轴突中缓慢的轴突运输成分有关。这个项目的目标是利用细胞生物学研究来评估在体外观察到的神经丝沿着微管的运动是否与神经丝沿着轴突在体内的运输有关。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，这一建议与衰老相关的细胞内转运机制的变化有关，这可能与神经退行性疾病中细胞骨架蛋白在神经元胞体中的异常积聚有关。

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.