Therapeutic strategies to rescue metabolic deficiencies in spinal and bulbar muscular atrophy

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Project Summary: Several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and the polyglutamine expansion diseases, result from protein misfolding and accumulation due to genetic and/or environmental causes. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, inherited (X-linked) neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related to other neurodegenerative diseases caused by polyglutamine expansion, including Huntington’s disease and several spinocerebellar ataxias. Although the precise pathways leading to neuronal dysfunction and death are unknown, the evaluation of mouse and cell models of these diseases has yielded mechanistic insights into disease pathogenesis. SBMA stands apart from other polyglutamine diseases in that its onset and progression are dependent on AR androgenic ligands. Metabolomic analyses of muscle and spinal cord from two mouse models of SBMA revealed severe reductions in muscle NAD+ while spinal cord showed no such changes. Treatment with nicotinamide riboside (NR) to restore NAD+ levels was unsuccessful. However, RNA-seq studies revealed substantially reduced levels of muscle NMRK2, which encodes an enzyme required to convert NR to NAD+ in muscle, suggesting a likely reason for both the reduction in NAD+ and its intransigence to NR treatment. We propose to bypass NRK2 through the systemic administration of nicotinamide mononucleotide (NMN) to two mouse models of SBMA with distinct expression patterns of polyglutamine-expanded androgen receptor but common defects in muscle NAD+ levels. The two mouse models of SBMA used within this proposal reproduce the androgen- and polyglutamine- dependent nuclear AR aggregation seen in patients, as well as its consequent toxicity, making studies using these models relevant to human SBMA patients. The successful completion of this study will reveal whether this simple therapeutic regimen could be beneficial for patients with SBMA.