| Authors |
Dabill LF, Shen IR, Brazill JM, Neiner A, Sasaki Y, Scheller EL
|
| Submitted By |
Submitted Externally on 8/18/2026 |
| Status |
Published |
| Journal |
FASEB journal : official publication of the Federation of American Societies for Experimental Biology |
| Year |
2026 |
| Date Published |
5/15/2026 |
| Volume : Pages |
40 : e71846 |
| PubMed Reference |
42068248 |
| Abstract |
SARM1 (sterile a and TIR motif-containing protein-1) is an NADase enzyme that
serves as the central executioner of Wallerian axon degeneration. Given this,
SARM1 is of high interest as a candidate therapeutic target, and SARM1
inhibitors are currently in clinical trials for treatment of neurodegeneration.
Beyond neuroscience, emerging studies reveal that SARM1 may also drive aspects
of bone fragility, liver pathology, adipose expansion, and insulin resistance in
metabolic disease. However, we lack methods to quantify SARM1 activation in
humans to better define patients at high risk of SARM1-mediated tissue damage.
Unlike neurons, peripheral blood mononuclear cells (PBMCs) represent an easily
accessible population for clinical screening. While SARM1 gene expression has
been identified in PBMCs, it is less known whether functional SARM1 NADase is
present. We hypothesized that by pairing activators and inhibitors of SARM1 with
analysis of downstream changes in cellular metabolites, we could identify and
quantify both basal SARM1 activity and the SARM1 activation potential of human
PBMCs. Our results reveal that SARM1 agonist pyrinuron, also known as Vacor,
activates a dose-dependent increase in cAPDR and the cADPR:ADPR ratio that is
arrested when paired with SARM1 inhibitor DSRM-3716. Changes in secondary
metabolites including NAD+, NMN, NaMN, ATP, AMP, IMP, inosine, and succinyl
adenosine were also characterized and used to generate a working model of PBMC
SARM1 activation. Overall, these findings demonstrate that human PBMCs have
detectable SARM1 activation potential and could be leveraged as a clinical
readout of SARM1 expression and activity across diverse disease contexts.
|
|
|