Yanmin Yang - US grants

DESCRIPTION (provided by applicant):The broad long-term goal is to elucidate the mechanisms responsible for the dysfunction and loss of neurons in degenerative neurological disorders. In BPAG1 null mouse, axonal degeneration of sensory neurons leads to dramatic and progressive deterioration in motor functions. This null mouse provides us a powerful tool for studying cellular and molecular mechanisms of neurodegeneration. Defining the biological functions of BPAG1 would significantly advance our understanding of pathogenesis. In previous studies, we documented BPAG1n1 and BPAG1n3, which function as cytoskeleton organizing proteins interconnecting all three networks. Most recently, we identified an additional isoform of BPAG1, BPAG1n4, whose functional importance has been suggested by our preliminary studies. We hypothesize that BPAG1n4 plays an important role in axonal transport of vesicles. Ablation of BPAG1 neuronal isoforms leads to disorganization of axonal cytoskeletal networks, disruption of axonal transport of vesicles and failure of target-derived neurotrophic support. This defect culminates in the death of affected neurons. The first AIM will further examine and confirm the subcellular localization of BPAG1n4 at the ultrastructural level. The second AIM is to characterize all potential functions of BPAG1n4. The functional interactions between BPAG1n4 and cytoskeletal proteins will be explored both in vitro and in vivo. The third AIM is to identify the proteins with which BPAG1n4 interact with. The proposed study will enhance our understanding of the biological functions of cytoskeletal organizing proteins in axons and their role(s) in sustaining neuronal survival. We expect to obtain important insights regarding the molecular pathogenesis of the death of neurons that have been deprived of target innervations. Our findings wilt lead to a better understanding and possible treatment for neurodegenerative disorders.

DESCRIPTION (provided by applicant): The broad long-term goal is to elucidate the molecular mechanisms responsible for the dysfunction and loss of neurons in degenerative neurological disorders. In BPAG1 null mouse, axonal degeneration of sensory neurons leads to dramatic and progressive deterioration in motor functions. This null mouse provides us a powerful tool for studying cellular and molecular mechanisms of neurodegeneration. Defining the biological functions of BPAG1 would significantly advance our understanding of pathogenesis. In previous studies, we documented BPAG1n1 and BPAG1n3, which function as cytoskeleton organizing proteins interconnecting all 3 networks. Most recently, we identified an additional isoform of BPAG1, BPAG1n4, whose functional importance has been suggested by our preliminary studies. We hypothesize that BPAG1n4 plays an important role in axonal transport of vesicles. Ablation of BPAG1 neuronal isoforms leads to disorganization of axonal cytoskeletal networks, disruption of axonal transport of vesicles and failure of target-derived neurotrophic support. This defect culminates in the death of affected neurons. The first Aim will further examine and confirm the sub-cellular localization of BPAG1n4 at the ultrastructural level. The second Aim is to characterize all potential functions of BPAG1n4. The functional interactions between BPAG1n4 and cytoskeletal proteins will be explored both in vitro and in vivo. The third Aim is to identify the proteins with which BPAG1n4 interact with by using yeast two-hybrid system. The proposed study will enhance our understanding of the biological functions of cytoskeletal organizing proteins in axons and their role(s) in sustaining neuronal survival. We expect to obtain important insights regarding the molecular pathogenesis of the death of neurons that have been deprived of target innervations. Our findings will lead to a better understanding and possible treatment for neurodegenerative disorders. I believe that my research focus will provide a wonderful fusion of my interest in understanding the development and function of nervous system and my desire to help people and to explore the disease mechanisms. The Department of Neurology at Stanford University provides an ideal environment for developing my academic career into a leading investigator in the neurobiology of disease.

DESCRIPTION (provided by applicant): Angelman syndrome (AS) is a rare genetic disorder that results in severe mental retardation and a host of other cognitive, movement, and behavioral symptoms. Mutations in the UBE3A gene lead to dysfunction of the ubiquitin ligase, E6-AP (E6 associated protein). While the UBE3A gene product is found in a broad range of tissues, its expression is specifically imprinted in a subset of neurons in brain. The majority of patient mutations identified to date perturb E6-AP's catalytic activity or capacity to associate with cognate E2s, implying that disruption of its E3 ligase function must be critical to the development of AS. We hypothesize that dysfunction of E6-AP in the disorder causes impaired UPS function, leading to abnormal neuronal accumulations of crucial, unidentified substrates that play a critical role in disease pathogenesis. We propose to identify and verify candidates that are E6-AP substrates. AS is the consequence of disruption of a single pleiotropic gene, resulting in profound mental retardation and a host of additional, devastating symptoms. Identification of E6-AP substrates that accumulate due to defective protein processing is a critical first step to determine the molecular pathways disrupted in AS, and could lead to the development of treatments for it and other related disorders. PUBLIC HEALTH RELEVANCE: Neurodegenerative problems associated with cognition, movement, and behavior of the aging population are becoming an increasing burden. We propose that Angelman Syndrome (AS), which is characterized by shared defects in these processes, results from abnormal accumulation of unidentified proteins caused by defective protein processing. Although the genetic defect underlying AS has been known since 1997, the identity of these accumulated proteins remains unknown. We propose to find the molecules and pathways that are disrupted in AS, which may lead to therapies to target more common symptoms of neurodegeneration.

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.