Characterizing mechanisms underlying neurodegeneration in GAN

GAN神经退行性变的机制研究 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。巨大轴突神经病是一种严重的运动和感觉神经病， 影响中枢神经系统和周围神经的神经病。截至目前，24 在人类GAN患者中已经鉴定出不同的突变。我们以前的研究 证明了gigaxonin通过泛素在蛋白质降解中起重要作用， 蛋白酶体依赖机制。问题是， 积累的蛋白质会导致毁灭性的后果：轴突变性， 神经元死亡，需要研究。拟议的项目是描述 GAN引起神经退行性变的病理途径和机制 破坏第一个目的是分析gigaxonin的无效小鼠。GAN的遗传模型 在小鼠中的紊乱可以让我们观察疾病的进展，进行彻底的 检查贯穿于整个病程，并分析病理 disorder.第二个目的是分析GAN敲除小鼠中的轴突运输。第三 目的是研究毒性积累如何导致 GAN中发生的神经变性。GAN的病理特征，包括 异常的细胞骨架组织、异常的线粒体形态和肿胀 轴突与泡状积聚，可以发现在许多人类神经 疾病对GAN病理通路的深入了解， 对其他退行性疾病的深入了解。

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.