Investigation of the role of PARP-1 and CD38 in modulating NAD+ levels in spinal and bulbar muscular atrophy

Date of Award


Degree Type


Degree Name

Master of Science in Biomedical Sciences

First Advisor

Heather L. Montie, PhD

Second Advisor

Denah M. Appelt, PhD

Third Advisor

Jocelyn J. Lippman-Bell, PhD


Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is an adult-onset neuromuscular condition that affects men. There is no cure or method to date to modify SBMA progression. In this study, we used a mouse model of SBMA (AR100Q) to determine the contribution of two enzymes to NAD+ levels, as this molecular fuel is dramatically reduced in SBMA. The first goal was to evaluate the level of an NAD+ consuming protein, PARP-1, in AR100Q mouse muscle and if reducing PARP-1 protein could increase NAD+ levels to improve skeletal muscle health. We have aged multiple cohorts of SBMA (AR100Q), AR24Q (control), and wild-type (WT) male mice, with either intact PARP-1, or with one or both missing alleles of PARP-1 (PARP-1 heterozygous (Het)). We identified that PARP-1 protein levels decrease in early disease (8 weeks) and are nearly undetectable by 11 weeks (late-stage disease). The loss of one or both PARP-1 alleles did not rescue NAD+ levels in these AR100Q mice. The lack of recovery of NAD+ levels with a loss of one allele of PARP-1 in AR100Q mice may be explained by our finding that PARP-1 protein levels decreased with disease progression. The second enzyme we investigated was the NADase, CD38, which also utilizes NAD+. Thus, we aimed to reduce CD38’s activity to increase NAD+ levels in skeletal muscle of mice modeling SBMA. The 6-hour treatment with a CD38 inhibitor (78c) resulted in a significant increase of NAD+ levels in AR100Q mouse muscle. Our studies identified CD38 as a potential modulator of NAD+ levels in SBMA and continued studies with further investigate the role of CD38 in SBMA pathogenesis.

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