Somatic instability of CAG repeats in spinal and bulbar muscular atrophy - Many neurodegenerative diseases, including Huntington’s disease, ALS, several adult-onset spinocerebellar ataxias, and spinal and bulbar muscular atrophy (SBMA) result from the inherited expansion of a repeated nucleotide sequence. Spinal and bulbar muscular atrophy (SBMA) is an adult- onset, inherited neuromuscular disease that is caused by polyglutamine-encoding CAG nucleotide repeat expansion within the androgen receptor (AR) gene; it is related to other neurodegenerative diseases caused by polyglutamine-encoding CAG expansion, including Huntington’s disease and several spinocerebellar ataxias. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded mechanistic insights to disease pathogenesis. SBMA stands apart from other polyglutamine diseases in that its onset and progression are dependent on AR androgenic ligands; therefore, SBMA exclusively affects men. Many cell and mouse models of SBMA reproduce the androgen- and polyglutamine- dependent nuclear AR aggregation seen in patients, as well as its consequent toxicity, making these models highly useful for the analysis of the mechanistic basis for upstream events involved in AR toxicity. Our long-term objectives are to use these models to develop a mechanistic understanding of SBMA pathogenesis and to develop therapeutic approaches based on that understanding. Recent studies have revealed that SBMA symptoms do not result exclusively from the dysfunction and ultimate death of spinal motor neurons. Rather, SBMA results from deficits in the neuromuscular system, with both myogenic and neurogenic pathology observed in affected muscles. Recent advances in the role of somatic CAG repeat instability in Huntington’s disease and mechanistic insights into the role for mismatch repair pathway in somatic instability prompted our re-evaluation of somatic instability in SBMA. Our preliminary data reveal somatic expansions in muscles but not in spinal cord of a knock-in mouse model of SBMA and in autopsy material from human SBMA patients. Moreover, AR CAG expansions in mouse muscles increase with age. We propose in this application to evaluate the tissue selectivity and temporal relationship of somatic instability in aging SBMA mice and in human SBMA muscle biopsies and to investigate the role of somatic expansion in the disease process. The outcomes from these studies are likely to reveal a novel mechanism contributing to SBMA and to identify new therapeutic directions.
