Characterizing mechanisms underlying neurodegeneration in GAN

描述（由申请人提供）：描述GAN中神经退行性疾病的潜在机制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。到目前为止，已经在人类GAN患者中确定了24种不同的突变。我们前期的研究表明，gigaxonin通过泛素-蛋白酶体依赖的机制在蛋白质降解中起重要作用.关于积累的蛋白质的毒性如何导致破坏性后果的问题：轴突变性和神经元死亡，需要研究。该项目旨在研究GAN破坏导致神经退行性变的病理途径和机制。第一个目的是分析gigaxonin的无效小鼠。这种小鼠GAN疾病的遗传模型将使我们能够观察疾病进展，在整个疾病过程中进行彻底检查，并分析疾病的病理学。第二个目的是分析GAN敲除小鼠中的轴突运输。第三个目的是研究毒性蓄积导致GAN发生神经变性的机制。GAN的病理特征包括异常的细胞骨架结构、异常的线粒体形态、肿胀的轴突和囊泡聚集，可以在许多人类神经系统疾病中发现。彻底了解GAN的病理通路可能为其他退行性疾病提供强有力的见解。公共卫生相关性：描述由各种GAN突变导致的神经退行性疾病的潜在机制项目叙述与老龄化人口的认知、运动和行为相关的神经退行性疾病问题正在成为越来越大的负担。该项目拟研究由不同GAN突变导致的神经退行性变的病理途径。GAN的病理特征包括异常的细胞骨架结构、异常的线粒体形态、肿胀的轴突和囊泡聚集，可以在许多人类神经系统疾病中发现。彻底了解GAN的病理通路可能为其他退行性疾病提供强有力的见解。这一发现可能会导致针对更常见的神经变性症状的治疗。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Characterizing mechanisms underlying neurodegeneration resulted from the various GAN-mutations Project Narrative Neurodegenerative problems associated with cognition, movement, and behavior of the aging population are becoming an increasing burden. The proposed project is to Study the pathological pathways of neurodegeneration resulted from distinct GAN mutations. 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. The finding may lead to therapies to target more common symptoms of neurodegeneration.