Neuronal microtubule regulation and aging

项目总结 神经元微管调节及其对衰老的自主和非自主影响) 衰老是发展包括阿尔茨海默病在内的神经退行性疾病的最大风险因素 (Ad)。神经元老化，定义为功能和结构的进行性丧失，使神经元容易患上 退化。微管(MT)调节在神经元中的关键作用强调了它的重要性 MT相关蛋白，如tau和tau样蛋白，其功能障碍导致神经变性。 令人惊讶的是，人们对MTS在正常衰老过程中的作用知之甚少。MT监管涉及到 多个水平的神经元功能和结构的维持，而MT的调节似乎也是一个 年龄依赖性神经退行性变的一般下游指标和效应因子。前因后果 MT缺陷与细胞功能障碍之间的关系尚不清楚。在线虫身上，已经证明了这一点 带有tau样重复序列(ptl-1)的蛋白质突变(tau/map2/MAP4的同源基因)导致缺陷 神经功能和与年龄相关的形态变化加速发生。另一方面 另一方面，也有研究表明，其他MT调节因子的突变会延迟与年龄相关的改变的发生。 这些数据表明，MTS的缺陷不仅与神经元老化有关，而且也与神经元老化有关。这个 这项拟议研究的目标是确定与神经元老化相关的MT状态的变化，并 描述MT缺陷影响神经功能的机制。初步数据显示基因突变 多种MT调节剂足以影响脂代谢和寿命。中心假设是 神经元MT聚合体的保存通过GAP延缓神经元衰老和延长寿命 交汇点。在目标1中，我们将测试MT聚合的丢失是否会导致神经元老化。在目标2中，我们将 检测神经元MT扰动是否通过缝隙连接调节寿命和外周脂肪代谢 发信号。将使用共聚焦成像、分子、生化和线虫遗传方法来实现 这些目标。从这项提案中产生的数据不仅将增加我们对 MT在神经元和器官衰老中的调节，但也可能导致新的靶点来延缓衰老 及其相关疾病。

PROJECT SUMMARY (Neuronal microtubule regulation and its autonomous and non-autonomous effects on aging) Aging is the greatest risk factor for developing neurodegenerative diseases including Alzheimer's Disease (AD). Neuronal aging, defined as a progressive loss of function and structure, predisposes neurons to degeneration. The importance of microtubule (MT) regulation in neurons is underscored by the critical role of MT-associated proteins, e.g. tau and tau-like proteins, whose dysfunction leads to neurodegeneration. Surprisingly, little is known about the role of MTs in the normal aging process. MT regulation is involved on several levels of neuronal function and maintenance of structure, and MT regulation also appears to be a general downstream indicator and effector in age-dependent neurodegeneration. The cause and effect relationship between MT defects and cellular dysfunction is not clear. In C. elegans, it has been demonstrated that mutations in protein with tau-like repeats (ptl-1), an ortholog of tau/MAP2/MAP4, leads to defective neuronal function and an accelerated occurrence of age-associated morphological changes. On the other hand, it has also been shown that mutations in other MT regulators delay the onset of age-related changes. These data show defects in MTs are not only associated with, but also contribute to, neuronal aging. The goals of this proposed study are to define changes in MT status associated with neuronal aging and to characterize mechanisms by which MT defects affect neuronal function. Preliminary data indicate mutations in multiple MT regulators are sufficient to influence lipid metabolism and lifespan. The central hypothesis is preservation of MT polymerization in neurons delays neuronal aging and promotes longevity through gap junctions. In Aim 1, we will test whether loss of MT polymerization causes neuronal aging. In Aim 2, we will test whether neuronal MT perturbation regulates longevity and peripheral lipid metabolism via gap junctional signaling. Confocal imaging, molecular, biochemical and C. elegans genetic approaches will be used to fulfil these aims. Data generated from this proposal will not only increase our understanding of the roles played by MT regulation in the neuronal and organismal aging, but also potentially lead to novel targets to delay aging and its associated diseases.