Novel Roles for the Ectoenzyme CD38 in the Maintenance of Transcriptional and Metabolic Homeostasis in Astrocytes.
| Title: | Novel Roles for the Ectoenzyme CD38 in the Maintenance of Transcriptional and Metabolic Homeostasis in Astrocytes. |
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| Authors: | Basak S; School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA.; Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, Virginia, USA.; Colafrancesco AM; Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Hernandez RD; School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA.; Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, Virginia, USA.; Department of Human Genetics, Emory University, Atlanta, Georgia, USA.; Wei X; School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA.; McMeekin LJ; Department of Neuroscience, Southern Research, Birmingham, Alabama, USA.; Dang D; Department of Human Genetics, Emory University, Atlanta, Georgia, USA.; Simmons M; Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Department of Neuroscience, Southern Research, Birmingham, Alabama, USA.; Browning JL; School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA.; Noel K; School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA.; Zhou F; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Lund FE; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Saad JS; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Watsen SG; School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA.; Pickrell AM; School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA.; Cowell RM; Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Department of Neuroscience, Southern Research, Birmingham, Alabama, USA.; Olsen ML; School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA. |
| Source: | Glia [Glia] 2026 Feb; Vol. 74 (2), pp. e70112. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8806785 Publication Model: Print Cited Medium: Internet ISSN: 1098-1136 (Electronic) Linking ISSN: 08941491 NLM ISO Abbreviation: Glia Subsets: MEDLINE |
| Imprint Name(s): | Publication: New York, NY : Wiley-Liss; Original Publication: New York : Alan R. Liss, Inc., c1988- |
| MeSH Terms: | Astrocytes*/metabolism ; ADP-ribosyl Cyclase 1*/metabolism ; ADP-ribosyl Cyclase 1*/genetics ; ADP-ribosyl Cyclase 1*/deficiency ; Homeostasis*/physiology ; Membrane Glycoproteins*/metabolism ; Membrane Glycoproteins*/genetics; NAD/metabolism ; Brain/metabolism ; Mesencephalon/metabolism ; Animals ; Mice ; Mice, Knockout ; Mice, Inbred C57BL ; Male |
| Abstract: | CD38 is an ectoenzyme that converts NAD+ to NAM to help maintain bioenergetic homeostasis. CD38 dysregulation and gene variation is reported in neurodegenerative conditions such as Parkinson's disease (PD) and Alzheimer's disease (AD), highlighting the need to better understand CD38 biology within the brain. 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 in the brain. RNA-sequencing of isolated astrocytes revealed numerous differentially expressed genes in Cd38+/- and Cd38-/- mice, with alterations in mitochondrial, metabolic, senescence-related, astrocyte reactivity, and other genes involved in PD and AD etiology. Furthermore, functional metabolic analysis of midbrain revealed changes in pyruvate oxidation, age-dependent increase of citrate synthase (CS) activity, and reduction of cytochrome c oxidase-to-CS ratio in Cd38 deficiency. These findings identify a novel role for astrocytes in the regulation of CD38-dependent NAD/NAM homeostasis in the brain and provide a framework for future studies evaluating the relationship between CD38 dysfunction, aging, and vulnerability of neuronal populations in neurodegenerative disease. Importantly, these studies underscore the necessity to better resolve the impact of CD38 deficiency on brain metabolism, considering ongoing clinical trials and discussions related to the use of CD38 modulators for the treatment of cancers, age-related decline, and neurodegenerative disease.; (© 2025 The Author(s). GLIA published by Wiley Periodicals LLC.) |
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| Grant Information: | R01 NS124037 United States NS NINDS NIH HHS; R01NS124037 United States NH NIH HHS; S10 RR026478 United States RR NCRR NIH HHS; P30 CA013148 United States CA NCI NIH HHS; 1S10RR026478 United States NH NIH HHS; T32 NS095775 United States NS NINDS NIH HHS; T32NS09.5775 United States NH NIH HHS |
| Contributed Indexing: | Keywords: RNA‐sequencing; aging; astrocyte; brain metabolism; mitochondria; neurodegeneration |
| Molecular Sequence: | GEO GSE272765 |
| Substance Nomenclature: | EC 3.2.2.6 (ADP-ribosyl Cyclase 1); EC 3.2.2.5 (Cd38 protein, mouse); 0U46U6E8UK (NAD); 0 (Membrane Glycoproteins) |
| Entry Date(s): | Date Created: 20251216 Date Completed: 20251216 Latest Revision: 20260514 |
| Update Code: | 20260515 |
| PubMed Central ID: | PMC12706826 |
| DOI: | 10.1002/glia.70112 |
| PMID: | 41400119 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural