Function of Nna1 in Neuronal Death and Axon Regeneration

描述（由申请人提供）：鉴定有助于神经元存活的新机制和神经元产生再生反应的能力对于更好地理解和治疗从神经创伤到许多神经退行性疾病的病症具有广泛的意义。在这里，我们专注于Nna 1，一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。Nna 1的功能丧失突变导致小鼠的神经变性，其可能由对人类未知病因的神经变性疾病具有重大影响的前所未有的机制介导。在随后的合作研究中，确定了Nna 1突变导致经典常染色体隐性突变小鼠浦肯野细胞变性（pcd）的神经退行性表型。因此，Nna 1的表达增强与CNS中的再生反应相关，而Nna 1的功能丧失突变导致神经变性。最近，申请人的实验室证明，Nna 1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。这开启了影响这些基因的遗传病变可能导致更广泛类别的神经元变性的可能性，并且这些酶的内源性或环境抑制剂将加速神经变性。由于Nna 1的功能及其作用途径尚不清楚，对其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小鼠中确定了一个分子事件，这是这些动物中已知的最早的缺陷，可能直接将Nna 1与神经元死亡联系起来。本申请提出了三个具体目标，将定义Nna 1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的能力，以拯救浦肯野细胞损失pcd 3 J突变体通过重新表达Nna 1与L7/pcp 2启动子，我们的演示一个潜在的神经毒性内源性逆转录病毒样元件在pcd小鼠和结构信息获得的鉴定一个新的Nna 1相关基因的亚家族，以确定Nna 1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.