Novel roles for the ectoenzyme CD38 in the maintenance of transcriptional and metabolic homeostasis in astrocytes

CD38 is an ectoenzyme that converts NAD+ to NAM and helps to maintain bioenergetic homeostasis. A better understanding of CD38 biology in the brain is needed, considering the evidence for CD38 dysregulation and/or gene variation in neurodegenerative conditions such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). Here, we demonstrate enrichment of Cd38 in midbrain astrocytes and describe how CD38 deficiency influences brain metabolism, astrocytic gene expression, and bioenergetics. We demonstrate increased NAD content, decreased NAM content, and increased NAD/NAM in the midbrain and striatum of CD38-deficient (Cd38-/-) mice, indicating the dependence on CD38 for NAD to NAM conversion. RNA-sequencing of isolated astrocytes revealed numerous differentially expressed genes in Cd38+/- and Cd38-/- mice, with alterations in mitochondrial, metabolic, and senescence-related genes and several genes involved in PD and AD etiology. Interestingly, Seahorse XFe24 mitochondrial functional evaluation in primary astrocyte cultures from Cd38+/+, Cd38+/-, and Cd38-/- mice revealed enhanced oxygen consumption, with an increase in glycolytic rate with Cd38 deficiency. These findings indicate a novel role for astrocytes in the regulation of CD38-dependent NAD/NAM homeostasis in the brain and provide the framework for future studies evaluating the relationship between CD38 dysfunction, aging, and vulnerability of neuronal populations in neurodegenerative disease. Also, these studies highlight the need to better elucidate the impact of CD38 deficiency on brain metabolism, considering ongoing clinical trials using CD38 inhibitors for the treatment of multiple myeloma and other cancers.