Characterizing mechanisms underlying neurodegeneration in GAN

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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.