Molecular Mechanism of Imac-dependent axonal transport

描述(申请人提供)：复杂神经网络的正确功能依赖于特定突触连接的发展和稳定。在发育性和神经退行性疾病中，正常突触结构和功能的紊乱在疾病的病理中起着核心作用。由于神经元的特殊形态，蛋白质和细胞器沿细胞骨架丝的主动运输被证明不仅对细胞存活、轴突生长和突触形成至关重要。此外，运动蛋白分子马达超家族与神经退行性疾病有关：肌萎缩侧索硬化症、亨廷顿病和帕金森病。在果蝇中，我们的实验室发现了kinesin-3家族成员imac，它是突触发生所必需的运动。在iMac缺失突变体中，轴突到达合适的靶点，但不能形成突触，活动区减少，末端缺乏突触小泡。Imac在整个神经系统和动物的整个生命中普遍表达，这表明在胚胎突触成熟的初始阶段之后，突触货物的运输仍然发挥着作用。利用果蝇遗传学，这一建议旨在表征幼虫发育过程中iMac依赖的突触添加运输功能，以确定突触货物的主动运输是否需要突触维持。此外，我们将进行结构功能分析和生物化学，以确定与IMAC相关的蛋白质，以调节运输和促进货物结合。我们的长期目标是进一步了解调节突触发育和维持的分子机制。

DESCRIPTION (provided by applicant): The proper function of complex neural networks relies on the development and stabilization of specific synaptic connections. In both developmental and neurodegenerative disorders disruption of proper synaptic structure and function plays a central role in the pathology of the disease. Due to the specialized morphology of neurons, active transport of proteins and organelles along cytoskeletal filaments has proven to be critical not only for cell survival, axon outgrowth but also synaptogenesis. Moreover, the kinesin superfamily of molecular motors has been implicated the neurodegenerative disorders: Amyotrophic Lateral Sclerosis, Huntington disease and Parkinson's disease. In Drosophila melangastor, our lab identified the kinesin-3 family member, Imac, to be an essential motor for synaptogenesis. In imac null mutants, axons reach their proper targets but fail to form boutons, have decreased active zones and lack synaptic vesicles at the terminals. Imac is ubiquitously expressed throughout the nervous system and throughout the life of the animal suggesting a continued role for the transport of synaptic cargo after the initial stage of synaptic maturation i the embryo. Using Drosophila genetics, this proposal aims to characterize the function of Imac-dependent transport for synapse addition during larval development, to determine if active transport of synaptic cargo is required synapse maintenance. Additionally, we will perform structure function analysis and biochemistry to identify proteins that associate with Imac to regulate trafficking and facilitate cargo binding. Our long-term goal is to further our understanding of the molecular mechanisms that regulate synapse development and maintenance.