Characterizing BPAG1n4, a Sensory Neuron's Sustainer

描述（由申请人提供）：广泛的长期目标是阐明退行性神经系统疾病中神经元功能障碍和丢失的机制。在BPAG 1基因敲除小鼠中，感觉神经元的轴突变性导致运动功能的显著和进行性恶化。这种无效小鼠为我们研究神经退行性变的细胞和分子机制提供了有力的工具。确定BPAG1的生物学功能将大大促进我们对发病机制的理解。在以前的研究中，我们记录了BPAG1n1和BPAG1n3，它们作为细胞骨架组织蛋白将所有三个网络连接起来。最近，我们确定了一个额外的亚型BPAG1，BPAG1n4，其功能的重要性已建议我们的初步研究。我们推测BPAG1n4在囊泡的轴突运输中起着重要作用。BPAG 1神经元亚型的消融导致轴突细胞骨架网络的解体，囊泡轴突运输的破坏和靶源性神经营养支持的失败。这种缺陷最终导致受影响的神经元死亡。第一个AIM将在超微结构水平上进一步检查和确认BPAG1n4的亚细胞定位。第二个目的是表征BPAG 1n4的所有潜在功能。BPAG1n4和细胞骨架蛋白之间的功能相互作用将在体外和体内进行探索。第三个目的是鉴定与BPAG 1n4相互作用的蛋白质。这项研究将加深我们对轴突中细胞骨架组织蛋白的生物学功能及其在维持神经元存活中的作用的理解。我们期望获得重要的见解，关于已被剥夺了目标神经支配的神经元死亡的分子发病机制。我们的发现将导致更好地理解和可能的治疗神经退行性疾病。

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.