Function of Nna1 in Neuronal Death and Axon Regeneration

描述(申请人提供)：识别有助于神经元存活的新机制和神经元启动再生反应的能力对于更好地理解和治疗从神经创伤到一系列神经退行性疾病的疾病具有广泛的意义。在这里，我们关注NNA1，这是一种代表神经元死亡和再生之间意想不到的独特机制联系的蛋白质。NNA1功能突变的丧失导致了小鼠的神经变性，这可能是由一种前所未有的机制介导的，这种机制对人类不明原因的神经退行性疾病具有重要意义。NNA1是在申请人的实验室中发现的，是一种在手术后脊髓运动神经元中诱导的基因。在随后的一项合作研究中，NNA1的突变被证实导致了经典的常染色体隐性突变小鼠的神经退行性变表型，浦肯野细胞变性(PCD)。因此，NNA1的表达增强与中枢神经系统的再生反应有关，而NNA1功能缺失突变会导致神经变性。最近，申请人的实验室证明，NNA1定义了一个新的M14羧肽酶亚家族，具有独特的结构和细胞位置。这开启了一种可能性，即影响这些基因的遗传损伤可能会导致更广泛类别的神经元退化，而这些酶的内源性或环境抑制物将导致神经退化。由于NNA1的功能和作用途径尚不清楚，它们的阐明将为神经退行性变和再生机制提供新的见解。我们已经在PCD小鼠中发现了一个分子事件，这是这些动物中已知的最早的缺陷，可能直接将NNA1与神经元死亡联系起来。这项申请提出了三个特定的目标，将定义NNA1的生化功能及其在小脑神经元死亡中的作用。这些目标将利用我们通过L7/PCP2启动子重新表达NNA1来挽救pcd3J突变体中Purkinje细胞损失的能力，我们证明了在PCD小鼠中潜在的神经毒性内源性逆转录病毒样元件的激活，以及通过鉴定新的NNA1相关基因亚家族获得的结构信息来定义NNA1的生化和细胞生物学特性。

DESCRIPTION (provided by applicant): The identification of novel mechanisms that contribute to neuronal survival and the ability of neurons to mount regenerative responses have broad implications for a better understanding and treatment of conditions ranging from neural trauma to a host of neurodegenerative disorders. Here, we focus on Nna1, a protein that represents an unexpected and unique mechanistic link between neuronal death and regeneration. Loss of function mutations in Nna1 lead to neurodegeneration in mice that may be mediated by an unprecedented mechanism that has major implications for neurodegenerative disorders of unknown etiology in man. Nna1 was discovered in the applicant's laboratory as a gene induced in spinal motor neurons following surgical axotomy. In a subsequent collaborative study it was established that mutations in Nna1 caused the neurodegenerative phenotype in the classical autosomal recessive mutant mouse, Purkinje cell degeneration (pcd). Thus, enhanced expression of Nna1 is associated with regenerative responses in the CNS whereas loss-of-function mutations in Nna1 result in neurodegeneration. Recently, the applicant's laboratory demonstrated that Nna1 defined a new subfamily of M14 carboxypeptidases with unique aspects of structure and cellular location. This opens the possibility that genetic lesions that affect these genes may cause degeneration of broader categories of neurons and that endogenous or environmental inhibitors of these enzymes will precipitate neurodegeneration. As the function of Nna1 and the pathway in which it acts are unknown their elucidation will provide new insights into mechanisms of neurodegeneration and regeneration. We have identified a molecular event in pcd mice that is the earliest known deficit in these animals and that may directly link Nna1 to neuronal death. This application proposes three specific aims that will define the biochemical function of Nna1 and its role in neuronal death in cerebellum. These aims will exploit our ability to rescue Purkinje cell loss in pcd3J mutants by re-expressing Nna1 with the L7/pcp2 promoter, our demonstration of the activation of a potentially neurotoxic endogenous retroviral like element in pcd mice and structural information obtained from the identification of a subfamily of novel Nna1-related genes to define the biochemical and cell biological properties of Nna1.