TY - JOUR
T1 - SARM1 detection in myelinating glia
T2 - sarm1/Sarm1 is dispensable for PNS and CNS myelination in zebrafish and mice
AU - Fazal, Shaline V.
AU - Mutschler, Clara
AU - Chen, Civia Z.
AU - Turmaine, Mark
AU - Chen, Chiung Ya
AU - Hsueh, Yi Ping
AU - Ibañez-Grau, Andrea
AU - Loreto, Andrea
AU - Casillas-Bajo, Angeles
AU - Cabedo, Hugo
AU - Franklin, Robin J.M.
AU - Barker, Roger A.
AU - Monk, Kelly R.
AU - Steventon, Benjamin J.
AU - Coleman, Michael P.
AU - Gomez-Sanchez, Jose A.
AU - Arthur-Farraj, Peter
N1 - Publisher Copyright:
Copyright © 2023 Fazal, Mutschler, Chen, Turmaine, Chen, Hsueh, Ibañez-Grau, Loreto, Casillas-Bajo, Cabedo, Franklin, Barker, Monk, Steventon, Coleman, Gomez-Sanchez and Arthur-Farraj.
PY - 2023
Y1 - 2023
N2 - Since SARM1 mutations have been identified in human neurological disease, SARM1 inhibition has become an attractive therapeutic strategy to preserve axons in a variety of disorders of the peripheral (PNS) and central nervous system (CNS). While SARM1 has been extensively studied in neurons, it remains unknown whether SARM1 is present and functional in myelinating glia? This is an important question to address. Firstly, to identify whether SARM1 dysfunction in other cell types in the nervous system may contribute to neuropathology in SARM1 dependent diseases? Secondly, to ascertain whether therapies altering SARM1 function may have unintended deleterious impacts on PNS or CNS myelination? Surprisingly, we find that oligodendrocytes express sarm1 mRNA in the zebrafish spinal cord and that SARM1 protein is readily detectable in rodent oligodendrocytes in vitro and in vivo. Furthermore, activation of endogenous SARM1 in cultured oligodendrocytes induces rapid cell death. In contrast, in peripheral glia, SARM1 protein is not detectable in Schwann cells and satellite glia in vivo and sarm1/Sarm1 mRNA is detected at very low levels in Schwann cells, in vivo, in zebrafish and mouse. Application of specific SARM1 activators to cultured mouse Schwann cells does not induce cell death and nicotinamide adenine dinucleotide (NAD) levels remain unaltered suggesting Schwann cells likely contain no functionally relevant levels of SARM1. Finally, we address the question of whether SARM1 is required for myelination or myelin maintenance. In the zebrafish and mouse PNS and CNS, we show that SARM1 is not required for initiation of myelination and myelin sheath maintenance is unaffected in the adult mouse nervous system. Thus, strategies to inhibit SARM1 function to treat neurological disease are unlikely to perturb myelination in humans.
AB - Since SARM1 mutations have been identified in human neurological disease, SARM1 inhibition has become an attractive therapeutic strategy to preserve axons in a variety of disorders of the peripheral (PNS) and central nervous system (CNS). While SARM1 has been extensively studied in neurons, it remains unknown whether SARM1 is present and functional in myelinating glia? This is an important question to address. Firstly, to identify whether SARM1 dysfunction in other cell types in the nervous system may contribute to neuropathology in SARM1 dependent diseases? Secondly, to ascertain whether therapies altering SARM1 function may have unintended deleterious impacts on PNS or CNS myelination? Surprisingly, we find that oligodendrocytes express sarm1 mRNA in the zebrafish spinal cord and that SARM1 protein is readily detectable in rodent oligodendrocytes in vitro and in vivo. Furthermore, activation of endogenous SARM1 in cultured oligodendrocytes induces rapid cell death. In contrast, in peripheral glia, SARM1 protein is not detectable in Schwann cells and satellite glia in vivo and sarm1/Sarm1 mRNA is detected at very low levels in Schwann cells, in vivo, in zebrafish and mouse. Application of specific SARM1 activators to cultured mouse Schwann cells does not induce cell death and nicotinamide adenine dinucleotide (NAD) levels remain unaltered suggesting Schwann cells likely contain no functionally relevant levels of SARM1. Finally, we address the question of whether SARM1 is required for myelination or myelin maintenance. In the zebrafish and mouse PNS and CNS, we show that SARM1 is not required for initiation of myelination and myelin sheath maintenance is unaffected in the adult mouse nervous system. Thus, strategies to inhibit SARM1 function to treat neurological disease are unlikely to perturb myelination in humans.
KW - SARM1
KW - Schwann cell
KW - mouse
KW - myelination
KW - oligodendrocyte
KW - zebrafish
UR - http://www.scopus.com/inward/record.url?scp=85153107753&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85153107753&partnerID=8YFLogxK
U2 - 10.3389/fncel.2023.1158388
DO - 10.3389/fncel.2023.1158388
M3 - Article
AN - SCOPUS:85153107753
SN - 1662-5102
VL - 17
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
M1 - 1158388
ER -