Investigation of the role of PARP-1 and CD38 in modulating NAD+ levels in spinal and bulbar muscular atrophy
Date of Award
Master of Science in Biomedical Sciences
Heather L. Montie, PhD
Denah M. Appelt, PhD
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.
Lozzi, Caroline E., "Investigation of the role of PARP-1 and CD38 in modulating NAD+ levels in spinal and bulbar muscular atrophy" (2022). PCOM Biomedical Studies Student Scholarship. 220.