Characterizing mechanisms underlying neurodegeneration in GAN

GaN神经退行性变机制的研究 摘要 阐明神经退行性疾病的细胞和分子机制 是我的研究重点。巨大轴索神经病是一种严重的运动和感觉疾病 同时影响中枢神经系统和周围神经的神经病。最新，24 已经在人类GAN患者中发现了明显的突变。我们之前的研究 证明了通过泛素在蛋白质降解中发挥重要作用的-- 蛋白酶体依赖机制。关于它的毒性如何 积累的蛋白质会导致毁灭性的后果：轴突变性和 神经细胞死亡，需要调查。拟议的项目是为了描述 肝硬化性神经变性的病理途径和机制 颠覆。第一个目标是分析神经生长素缺失的小鼠。GaN的这种遗传模式 在小鼠的紊乱中，我们可以观察疾病的进展，进行彻底的 在整个疾病过程中进行检查，并分析 无序。第二个目的是分析GaN基因缺失小鼠的轴突运输。第三 目的是研究毒素积累是如何导致 GaN中发生的神经退行性变。GaN的病理特征包括 细胞骨架组织异常，线粒体形态异常，肿胀 在许多人类神经系统中都可以发现有囊泡堆积的轴突。 疾病。彻底了解GaN的病理途径可能会提供 对其他退行性疾病有很强的洞察力。

Characterizing mechanisms underlying neurodegeneration in GAN Abstract Elucidating cellular and molecular mechanisms underlying neurodegenerative disorders is my research focus. Giant axonal neuropathy is a severe motor and sensory neuropathy affecting both central nervous system and peripheral nerves. Up to date, 24 distinct mutations have been identified in human GAN patients. Our previous studies demonstrated that gigaxonin plays an important role in protein degradation via ubiquitin- proteasome dependent mechanisms. The question regarding how the toxicities of accumulated proteins lead to a devastating consequence: axonal degeneration and neuronal death, needs to be investigated. The proposed project is to characterize the pathological pathways and mechanisms of neurodegeneration resulted from GAN's disruption. The first aim is to analyze gigaxonin's null mice. This genetic model of GAN disorder in mice will allow us to observe the disease progress, to conduct a thorough examination throughout the entire disease course, and to analyze the pathology of the disorder. The second aim is to analyze axonal transport in the GAN null mice. The third aim is to investigate mechanisms how the toxic accumulation causes neurodegeneration occurring in GAN. The pathological hallmarks of GAN, including aberrant cytoskeletal organizations, abnormal morphology of mitochondria, and swollen axons with vesicular accumulations, could be found in many human neurological diseases. Thorough understanding of the pathological pathway in GAN may provide strong insight into other degenerative diseases.