Selective neuronal degeneration is a distinguishing feature of many adult onset neurodegenerative disorders. Among these chronic diseases of the nervous system are ones caused by expansions of CAG/glutamine tracts. Kennedy disease, a member of this group, is characterized by degeneration of lower motor neurons due to an expanded CAG repeat in the first exon of the androgen receptor gene. Data from several laboratories including our own demonstrate that the mutant androgen receptor protein misfolds, aggregates and abnormally interacts with other proteins, leading to homone dependent lower motor neuron degeneration and skeletal muscle atrophy. Despite significant advances in unraveling the disease basis, pathways by which the mutant androgen receptor mediates selective motor neuron pathology remain inadequately understood. Recent work has highlighted the importance of abnormal cell interactions and the involvement of non-neuronal cells in the pathogenesis of certain polyglutamine and motor neuron diseases. The objective of this proposal is to identifiy the pathways by which the expanded glutamine androgen receptor causes selective neuronal loss. Our central hypothesis is that the mutant androgen receptor protein exerts toxic effects on both lower motor neurons and the skeletal muscle cells they innervate that together lead to selective neuronal pathology. This hypothesis is based on characterization of our recently developed knock-in mouse model of Kennedy disease. We find that this model reproduces the neuromuscular and systemic manifestations of this disorder. Furthermore, muscle pathology, which is accompanied by evidence of a primary myopathy and by activation of the unfolded protein response, precedes motor neuron loss, suggesting a role for non-cell autonomous toxicity. Biochemical, cellular and genetic approaches will be employed to gain a better understanding of the mechanisms leading to skeletal muscle pathology (Aim 1), the role of non-cell autonomous toxicity (Aim 2), and the contribution of the unfolded protein response to the development of the disease phenotype (Aim 3). The relevance of the proposed studies to public health is that they will provide new understanding of how proteins with expanded glutamine tracts cause neurodegeneration. This work is also expected to reveal insights into mechanisms leading to selective lower motor neuron dysfunction and death.
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