SARM1

SARM1 (sterile alpha and TIR motif containing 1) is an enzyme that is the most evolutionarily conserved member of the Toll-Interleukin receptor (TIR) family.[1] The enzyme is very similar in nematode worms, fruit flies, and humans, usually occurring in mitochondria.[1] But in mammals, SARM is highly expressed in neurons, located in primarily in axons rather than mitochondria.[1]

Function

Although SARM is known to participate in mitophagy and possibly other yet-unknown cell functions, its primary known function in mammals is mediation of neuronal cell death.[1] Because SARM1 is highly expressed in the nervous system, most studies of SARM1 focus on neuron degeneration, but some SARM1 can be found in many tissues. By cyclizing NAD+ to cADPR, SARM1 functions as a Ca2+-signaling enzyme similar to CD38, but SARM1 elevates cADPR much more efficiently than CD38.[2]

Wallerian degeneration
Main article: Wallerian degeneration

SARM1 in response to neuronal injury initiates a cell destruction program (Wallerian degeneration) that catalyze the formation of nicotinamide and adenosine diphosphate ribose (ADPR) or cyclic ADP-ribose (cADPR) from NAD+.[3][2][4] Similarly, SARM1 triggers cell death in the leaves of plants by a Toll-Interleukin receptor (TIR) domain NADase function.[5] Loss of SMAR1 in fruit flies and mice provides protection from axon degeneration.[6]

SARM1 protein plays a central role in the Wallerian degeneration pathway. The gene was first identified in a Drosophila melanogaster mutagenesis screen, and subsequently knockouts of its homologue in mice showed robust protection of transected axons comparable to that of WldS mutation (a mouse mutation resulting in slowed Wallerian degeneration).[7][8]

SARM1 activation locally triggers a rapid collapse of NAD+ levels in the distal section of the injured axon, which then undergoes degeneration.[9] This collapse in NAD+ levels was later shown to be due to SARM1's TIR domain having intrinsic NAD+ cleavage activity.[10] The SARM1 protein has four domains, a mitochondrial localization signal, an auto-inhibitory N-terminus region consisting of armadillo/HEAT motifs, two sterile alpha motifs responsible for multimerization, and a C-terminus Toll/Interleukin-1 receptor that possesses enzymatic activity.[10] Activation of SARM1 is sufficient to collapse NAD+ levels and initiate the Wallerian degeneration pathway.[9]

The activity of SARM1 helps to explain the protective nature of the survival factors NMNAT1 and NMNAT2, as NMNAT enzymes have been shown to prevent SARM1-mediated depletion of NAD+.[4][11] This relationship is further supported by the fact that mice lacking NMNAT2, which are normally not viable, are completely rescued by SARM1 deletion, placing NMNAT2 activity upstream of SARM1.[12] Other pro-degeneration signaling pathways, such as the MAP kinase pathway, have been linked to SARM1 activation. MAPK signaling has been shown to promote the loss of NMNAT2, thereby promoting SARM1 activation, although SARM1 activation also triggers the MAP kinase cascade, indicating some form of feedback loop exists.[13][14]

One explanation for the protective effect of the WldS mutation is that the NMNAT1 region, which is normally localized to the soma, substitutes for the labile survival factor NMNAT2 to prevent SARM1 activation when the N-terminal Ube4 region of the WldS protein localizes it to the axon. The axon-protective phenotype of WldS mutation is linked to enhanced expression of NMNAT1.[15] The fact that the enhanced survival of WldS axons is due to the slower turnover of WldS compared to NMNAT2 also helps explain why SARM1 knockout confers longer protection, as SARM1 will be completely inactive regardless of inhibitor activity whereas WldS will eventually be degraded. Possibles implications of the SARM1 pathway in regard to human health may be found in animal models which exhibit traumatic brain injury, as mice which contain Sarm1 deletions in addition to WldS show decreased axonal damage following injury.[16] Specific mutations in NMNAT2 have linked the Wallerian degeneration mechanism to two neurological diseases.

References
  1. Carty M, Bowie AG (2019). "SARM: From immune regulator to cell executioner". Biochemical Pharmacology. 161: 52–62. doi:10.1016/j.bcp.2019.01.005. PMID 30633870.
  2. Lee HC, Zhao YJ (2019). "Resolving the topological enigma in Ca 2+ signaling by cyclic ADP-ribose and NAADP". Journal of Biological Chemistry. 294 (52): 19831–19843. doi:10.1074/jbc.REV119.009635. PMC 6937575. PMID 31672920.
  3. Rajman L, Chwalek K, Sinclair DA (2018). "Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence". Cell Metabolism. 27 (3): 529–547. doi:10.1016/j.cmet.2018.02.011. PMC 6342515. PMID 29514064.
  4. Cambronne XA, Kraus WL (2020). "Location, Location, Location: Compartmentalization of NAD + Synthesis and Functions in Mammalian Cells". Trends in Biochemical Sciences. 45 (10): 858–873. doi:10.1016/j.tibs.2020.05.010. PMC 7502477. PMID 32595066.
  5. Bayless AM, Nishimura MT (2020). "Enzymatic Functions for Toll/Interleukin-1 Receptor Domain Proteins in the Plant Immune System". Frontiers in Genetics. 11: 539. doi:10.3389/fgene.2020.00539. PMC 7282519. PMID 32582284.
  6. Figley MD, DiAntonio A (2020). "The SARM1 axon degeneration pathway: control of the NAD + metabolome regulates axon survival in health and disease". Current Opinion in Neurology. 63: 59–66. doi:10.1016/j.conb.2020.02.012. PMC 7483800. PMID 32311648.
  7. Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, MacDonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH, Conforti L, Coleman M, Tessier-Lavigne M, Züchner S, Freeman MR (July 2012). "dSarm/Sarm1 is required for activation of an injury-induced axon death pathway". Science. 337 (6093): 481–4. Bibcode:2012Sci...337..481O. doi:10.1126/science.1223899. PMC 5225956. PMID 22678360.
  8. Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J (August 2013). "Sarm1-mediated axon degeneration requires both SAM and TIR interactions". The Journal of Neuroscience. 33 (33): 13569–80. doi:10.1523/JNEUROSCI.1197-13.2013. PMC 3742939. PMID 23946415.
  9. Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J (April 2015). "SARM1 activation triggers axon degeneration locally via NAD⁺ destruction". Science. 348 (6233): 453–7. Bibcode:2015Sci...348..453G. doi:10.1126/science.1258366. PMC 4513950. PMID 25908823.
  10. Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J (March 2017). "+ Cleavage Activity that Promotes Pathological Axonal Degeneration". Neuron. 93 (6): 1334–1343.e5. doi:10.1016/j.neuron.2017.02.022. PMC 6284238. PMID 28334607.
  11. Sasaki Y, Nakagawa T, Mao X, DiAntonio A, Milbrandt J (October 2016). "+ depletion". eLife. 5. doi:10.7554/eLife.19749. PMC 5063586. PMID 27735788.
  12. Gilley J, Ribchester RR, Coleman MP (October 2017). "S, Confers Lifelong Rescue in a Mouse Model of Severe Axonopathy". Cell Reports. 21 (1): 10–16. doi:10.1016/j.celrep.2017.09.027. PMC 5640801. PMID 28978465.
  13. Yang J, Wu Z, Renier N, Simon DJ, Uryu K, Park DS, Greer PA, Tournier C, Davis RJ, Tessier-Lavigne M (January 2015). "Pathological axonal death through a MAPK cascade that triggers a local energy deficit". Cell. 160 (1–2): 161–76. doi:10.1016/j.cell.2014.11.053. PMC 4306654. PMID 25594179.
  14. Walker LJ, Summers DW, Sasaki Y, Brace EJ, Milbrandt J, DiAntonio A (January 2017). "MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2". eLife. 6. doi:10.7554/eLife.22540. PMC 5241118. PMID 28095293.
  15. Jadeja RN, Thounaojam MC, Martin PM (2020). "Implications of NAD + Metabolism in the Aging Retina and Retinal Degeneration". Oxidative Medicine and Cellular Longevity. 2020: 2692794. doi:10.1155/2020/2692794. PMC 7238357. PMID 32454935.
  16. Henninger N, et al. (2016). "Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1". Brain. 139 (4): 1094–1105. doi:10.1093/brain/aww001. PMC 5006226. PMID 26912636.
  • SARM1 (Wikigenes collaborative publishing)
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