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(searched for: doi:10.1038/s41598-020-78896-w)
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Ciara G. Doran, Ryoichi Sugisawa, Michael Carty, Fiona Roche, Claire Fergus, , Vincent P. Kelly,
Published: 15 November 2021
Journal of Biological Chemistry; https://doi.org/10.1016/j.jbc.2021.101417

Abstract:
SARM1 is a TIR-domain containing protein, with roles proposed in both innate immunity and neuronal degeneration. Murine SARM1 has been reported to regulate the transcription of chemokines in both neurons and macrophages, however the extent to which SARM1 contributes to transcription regulation remains to be fully understood. Here, we identify differential gene expression in bone marrow-derived macrophages (BMDM) from C57BL/6 congenic 129 ES cell-derived Sarm1-/- mice compared to wild type (WT). However, we found passenger genes which are derived from the 129 donor strain of mice that flank the Sarm1 locus confound interpretation of the results, since many of the identified differentially regulated genes come from this region. To re-examine the transcriptional role of SARM1 in the absence of passenger genes, here we generated three Sarm1-/- mice using CRISPR/Cas9. Treatment of neurons from these mice with vincristine, a chemotherapeutic drug causing axonal degeneration, confirmed SARM1's function in that process; however, these mice also showed that lack of SARM1 has no impact on transcription of genes previously shown to be affected such as chemokines. To further insight into SARM1 function, we generated an epitope-tagged SARM1 mouse. In these mice, we observed high SARM1 protein expression in the brain and brainstem, and lower but detectable levels in macrophages. Overall, the generation of these SARM1 knockout and epitope-tagged mice has clarified that SARM1 is expressed in mouse macrophages yet has no general role in macrophage transcriptional regulation, and has provided important new models to further explore SARM1 function.
Esther H. Bae, , Ann G. Schwartz
Published: 21 October 2021
Neurotherapeutics pp 1-13; https://doi.org/10.1007/s13311-021-01142-2

The publisher has not yet granted permission to display this abstract.
Published: 30 September 2021
Neurotherapeutics pp 1-22; https://doi.org/10.1007/s13311-021-01125-3

Abstract:
Since Waller and Cajal in the nineteenth and early twentieth centuries, laboratory traumatic peripheral nerve injury studies have provided great insight into cellular and molecular mechanisms governing axon degeneration and the responses of Schwann cells, the major glial cell type of peripheral nerves. It is now evident that pathways underlying injury-induced axon degeneration and the Schwann cell injury-specific state, the repair Schwann cell, are relevant to many inherited and acquired disorders of peripheral nerves. This review provides a timely update on the molecular understanding of axon degeneration and formation of the repair Schwann cell. We discuss how nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha TIR motif containing protein 1 (SARM1) are required for axon survival and degeneration, respectively, how transcription factor c-JUN is essential for the Schwann cell response to nerve injury and what each tells us about disease mechanisms and potential therapies. Human genetic association with NMNAT2 and SARM1 strongly suggests aberrant activation of programmed axon death in polyneuropathies and motor neuron disorders, respectively, and animal studies suggest wider involvement including in chemotherapy-induced and diabetic neuropathies. In repair Schwann cells, cJUN is aberrantly expressed in a wide variety of human acquired and inherited neuropathies. Animal models suggest it limits axon loss in both genetic and traumatic neuropathies, whereas in contrast, Schwann cell secreted Neuregulin-1 type 1 drives onion bulb pathology in CMT1A. Finally, we discuss opportunities for drug-based and gene therapies to prevent axon loss or manipulate the repair Schwann cell state to treat acquired and inherited neuropathies and neuronopathies.
, Jeffrey Milbrandt, Matthew D. Figley
Published: 23 September 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.752898

Abstract:
The Toll/interleukin-1 receptor (TIR) domain is the signature signalling motif of innate immunity, with essential roles in innate immune signalling in bacteria, plants, and animals. TIR domains canonically function as scaffolds, with stimulus-dependent multimerization generating binding sites for signalling molecules such as kinases and ligases that activate downstream immune mechanisms. Recent studies have dramatically expanded our understanding of the TIR domain, demonstrating that the primordial function of the TIR domain is to metabolize NAD+. Mammalian SARM1, the central executioner of pathological axon degeneration, is the founding member of the TIR-domain class of NAD+ hydrolases. This unexpected NADase activity of TIR domains is evolutionarily conserved, with archaeal, bacterial, and plant TIR domains all sharing this catalytic function. Moreover, this enzymatic activity is essential for the innate immune function of these proteins. These evolutionary relationships suggest a link between SARM1 and ancient self-defense mechanisms that has only been strengthened by the recent discovery of the SARM1 activation mechanism which, we will argue, is strikingly similar to bacterial toxin-antitoxin systems. In this brief review we will describe the regulation and function of SARM1 in programmed axon self-destruction, and highlight the parallels between the SARM1 axon degeneration pathway and bacterial innate immune mechanisms.
, Mokhtar Ibrahim Yousef
Environmental Science and Pollution Research pp 1-13; https://doi.org/10.1007/s11356-021-16403-y

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Ciara G. Doran, Ryoichi Sugisawa, Michael Carty, Fiona Roche, Claire Fergus, Karsten Hokamp, Vincent P. Kelly,
Published: 25 August 2021
Abstract:
SARM1 is an ancient and highly conserved TIR-domain containing protein, with a diverse range of proposed roles in both innate immunity and neuronal death and degeneration. Murine SARM1 has been reported to regulate the transcription of specific chemokines in both neurons and macrophages, however the extent and mechanism by which SARM1 contributes to transcription regulation remains to be fully understood. Here, using RNA sequencing we identify differential gene expression in bone marrow-derived macrophages (BMDM) from C57BL/6 congenic 129 ES cell-derived Sarm1 -/- mice compared to wild type (WT). However, we show that passenger genes which are derived from the 129 donor strain of mice flank the Sarm1 locus, confounding interpretation of results, since many of the identified differentially regulated genes come from the region containing passenger genes. To re-examine the transcriptional role of SARM1 in the absence of such passenger genes, we generated three different Sarm1 -/- mice using CRISPR/Cas9 technology. Vincristine treatment of ex vivo cultured post-natal neurons from these mice confirmed SARM1’s previously identified key function as an executor of axon degeneration. However, using these mice, we show that the absence of SARM1 has no impact on transcription of genes previously shown to be altered in macrophages or in the brainstem. To gain further insight into SARM1 function, we generated and characterized a mouse expressing epitope-tagged SARM1, as it has been difficult to date to confirm which cells and tissues express SARM1 protein. In these mice we see high SARM1 protein expression in the brain and brainstem, and lower but detectable levels in macrophages. Overall, the generation of these next generation SARM1 knockout and epitope-tagged mice has clarified that SARM1 is expressed in mouse macrophages but has no general role in transcriptional regulation in these cells, and has provided important new animal models to further explore SARM1 function.
, Jian Zhu, Yun Shi, Weixi Gu, Bostjan Kobe, Thomas Ve, Aaron DiAntonio, Jeffrey Milbrandt
Published: 14 August 2021
Experimental Neurology, Volume 345; https://doi.org/10.1016/j.expneurol.2021.113842

The publisher has not yet granted permission to display this abstract.
, Jian Zhu, Yun Shi, Weixi Gu, Bostjan Kobe, Thomas Ve, Aaron DiAntonio, Jeffrey Milbrandt
Published: 16 July 2021
Abstract:
SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase. Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD+ related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD+ precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD+ precursor nicotinic acid mononucleotide (NaMN). We show that NaMN inhibits SARM1 activation, and demonstrate that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Analysis of the NaMN-ARM domain co-crystal structure shows that NaMN competes with NMN for binding to the SARM1 allosteric site and promotes the open, autoinhibited configuration of SARM1 ARM domain. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD+, and NaMN to monitor cellular NAD+ homeostasis and regulate SARM1 NAD+ hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders. Highlights NaMN binds to SARM1 N-terminal allosteric site and inhibits SARM1 NAD+ hydrolase NaMN inhibits SARM1 activation by stabilizing its open, inactive structure NMN deamidase promotes strong axonal protection by reducing NMN and increasing NaMN
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