Function of Nna1 in Neuronal Death and Axon Regeneration

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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.