Biology:SARM1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Sterile alpha and TIR motif containing 1 Is an enzyme that in humans is encoded by the SARM1 gene. It is the most evolutionarily conserved member of the Toll/Interleukin receptor-1 (TIR) family.[1][2] SARM1's TIR domain has intrinsic NADase enzymatic activity that is highly conserved from archaea, plants, nematode worms, fruit flies, and humans.[3][4][5] In mammals, SARM1 is highly expressed in neurons, where it resides in both cell bodies and axons, and can be associated with mitochondria.[6]

Function

While SARM1 has been studied as a Toll-like receptor adaptor protein in an immune context, its most well-studied function in mammals is as a sensor of metabolic stress and an executioner of neuronal cell body and axon death.[1][7][8][9][10][11] Because SARM1 is highly expressed in the nervous system, most studies of SARM1 focus on neuron degeneration, but some SARM1 can be found in other tissues, notably macrophages and T cells.[12][13] By generating cADPR or NAADP, SARM1 may function as a Ca2+-signaling enzyme similar to CD38.[14][15][16][17][18]

Regulation of enzymatic activity

SARM1's TIR domain is a multi-functional NAD(P)ase enzyme capable of hydrolyzing NAD+ or NADP, cyclizing NAD+ or NADP to form cADPR or cADPRP, and transglycosidation (base exchange) of NAD+ or NADP with free pyridines to form molecules such as NAADP.[2][4][19][16][20][17][21] For NAD+, The transglycosidation (base exchange) activity of SARM1 extends beyond simple pyridines and includes many heterocyclic nucleophilic bases.[22]

SARM1's enzymatic activity can be regulated at the TIR domain orthosteric site by naturally occurring metabolites such as nicotinamide, NADP, and nicotinic acid riboside.[2][17][23] Non-endogenous small chemical molecules have also been shown to inhibit SARM1's enzymatic activity at or near the orthosteric site.[22][24][25][26][27]

In addition, SARM1's enzymatic activity can be regulated by its allosteric site at the ARM domain, which can bind to NMN or NAD+.[9][22] The ratio of NMN/NAD+ in cells determines SARM1's enzymatic activity.[9][17][28][29][30] A chemically-modified cell permeable version of NMN, CZ-48, likely activates SARM1 via interacting with this allosteric region.[16][31] Two long-studied neurotoxins, Vacor and 3-acetylpyridine, cause neurodegeneration by activating SARM1. Both Vacor and 3-acetylpyridine can be modified by NAMPT to become their mononucleotide versions (Vacor-MN or 3-AP-MN) that bind to SARM1's allosteric ARM domain region and activate its TIR domain NADase activity.[32][33] When NAD+ levels are low, nicotinic acid mononucleotide (NaMN) can bind to the allosteric region and inhibit SARM1 activity,[34] thus explaining the potent axon protection provided by treating neurons with the NaMN precursor nicotinic acid riboside (NaR) while inhibiting NAMPT.[35] Chemical screening approaches have also identified covalent inhibitors of SARM1's allosteric ARM domain region.[20][36]

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.[37][38][39] SARM1 activation also triggers the MAP kinase cascade, indicating some form of feedback loop may exist.[40]

Relevance to human disease

Possible implications of the SARM1 pathway with regard to human health may be found in animal models of neurodegeneration, where loss of SARM1 is neuroprotective in models of traumatic brain injury,[41][42][43][44][45][27][46][47] chemotherapy-induced neuropathy,[48][49][50][25][51][52][27] diabetic neuropathy,[52][53] degenerative eye conditions,[54][55][56][57][58][59][60] drug-induced Schwann cell,[61] Charcot-Marie-Tooth disease,[62] and hereditary spastic paraplegia.[63]

Loss-of-function alleles of the SARM1 gene also occur naturally in the human population, potentially altering susceptibility to various neurological conditions.[64]

Specific mutations in the human NMNAT2 gene, encoding a key regulator of SARM1 activity, have linked the Wallerian degeneration mechanism to two human neurological diseases - fetal akinesia deformation sequence[65] and childhood-onset polyneuropathy with erythromelalgia.[66] Mutations in the human SARM1 gene that result in SARM1 protein with constitutive NADase activity have been reported in patients with amyotrophic lateral sclerosis (ALS).[67][68]

Wallerian degeneration pathway

Main page: Medicine:Wallerian degeneration

SARM1 protein plays a central role in the Wallerian degeneration pathway. The role for this gene in the Wallerian degeneration pathway was first identified in a Drosophila melanogaster mutagenesis screen,[7] and subsequently genetic knockout of its homologue in mice showed robust protection of transected axons comparable to that of WldS mutation (a mouse mutation resulting in delayed Wallerian degeneration).[7][8] Loss of SARM1 in human iPSC-derived neurons is also axon protective.[69]

The SARM1 protein has a mitochondrial localization signal, an auto-inhibitory N-terminus region consisting of armadillo (ARM)/HEAT motifs, two sterile alpha motif domains (SAM) responsible for multimerization, and a C-terminal Toll/Interleukin-1 receptor (TIR) domain that possesses enzymatic activity.[8] The functional unit of SARM1 is an octameric ring.[70] In healthy neurons, SARM1's enzyme activity is mostly autoinhibited through intramolecular and intermolecular interactions between ARM-ARM, ARM-SAM and ARM-TIR domains, as well as interactions between a duplex of octameric rings.[71][31][11][10][9][72]

SARM1's enzymatic activity is critically tuned to the activity of another axonal enzyme, NMNAT2. NMNAT2 is a labile protein in axons and is rapidly degraded after axon injury.[73] NMNAT2 is a transferase that uses ATP to convert nicotinamide mononucleotide (NMN) into NAD+. Remarkably, genetic loss of NMNAT2 in mice leads to embryonic lethality that can be fully rescued by genetic loss of SARM1, indicating that SARM1 acts downstream of NMNAT2.[74] Thus, when NMNAT2 is degraded after axon injury, SARM1 is activated. Conversely, overexpression of the WldS protein (which contains functional NMNAT1), axon-targeted NMNAT1, or NMNAT2 itself can protect axons and keep SARM1 from being activated.[75][76][77][78][79][80][81][82][83] These findings lead to the hypothesis and subsequent demonstration that NMNAT2's substrate NMN, which should increase when NMNAT2 is degraded after injury, can promote axon degeneration via SARM1.[84][85] Further studies revealed that NMN could activate SARM1's enzymatic activity.[16][31] Through a combination of structural, biochemical, biophysical, and cellular assays, it was revealed that SARM1 is tuned to NMNAT activity by sensing the ratio of NMN/NAD+.[9] This ratio is sensed by an allosteric region in SARM1's ARM domain region that can bind either NMN or NAD+. NAD+ binding is associated with SARM1's auto-inhibited state,[9][10][11] while NMN binding to the allosteric region results in a conformational change in the ARM domain that allows for multimerization of SARM1's TIR domains and enzymatic activation.[9][22][29][30]

SARM1 activation locally triggers a rapid collapse of NAD+ levels in the distal section of the injured axon, which then undergoes degeneration.[86] This collapse in NAD+ levels was later shown to be due to SARM1's TIR domain having intrinsic NAD+ cleavage activity.[2] SARM1 can hydrolyze NAD+ into nicotinamide and adenosine diphosphate ribose (ADPR), generate cyclic ADPR (cADPR), or mediate a base-exchange reaction with ADPR and free pyridine-ring containing bases, like nicotinamide.[2][15][16][17] Activation of SARM1's NADase activity is necessary and sufficient to collapse NAD+ levels and initiate the Wallerian degeneration pathway.[86][2] NAD+ loss is followed by depletion of ATP, defects in mitochondrial movement and depolarization, calcium influx, externalization of phosphatidylserine, and loss of membrane permeability prior to catastrophic axonal self-destruction.[87]

SARM1 activation due to loss of NMNAT2 in neurons also elicits a pro-degenerative neuroinflammatory response from peripheral nervous system macrophages and central nervous system astrocytes and microglia.[88][89][unreliable source]

References

  1. ↑ 1.0 1.1 "SARM: From immune regulator to cell executioner". Biochemical Pharmacology 161: 52–62. March 2019. doi:10.1016/j.bcp.2019.01.005. PMID 30633870. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration". Neuron 93 (6): 1334–1343.e5. March 2017. doi:10.1016/j.neuron.2017.02.022. PMID 28334607. 
  3. ↑ "TIR Domain Proteins Are an Ancient Family of NAD+-Consuming Enzymes". Current Biology 28 (3): 421–430.e4. February 2018. doi:10.1016/j.cub.2017.12.024. PMID 29395922. 
  4. ↑ 4.0 4.1 "TIR domains of plant immune receptors are NAD+-cleaving enzymes that promote cell death". Science 365 (6455): 799–803. August 2019. doi:10.1126/science.aax1771. PMID 31439793. Bibcode: 2019Sci...365..799W. 
  5. ↑ "TIR domain-containing adaptor SARM is a late addition to the ongoing microbe-host dialog". Developmental and Comparative Immunology 35 (4): 461–468. April 2011. doi:10.1016/j.dci.2010.11.013. PMID 21110998. 
  6. ↑ "Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism". Neuron 89 (3): 449–460. February 2016. doi:10.1016/j.neuron.2015.12.023. PMID 26844829. 
  7. ↑ 7.0 7.1 7.2 "dSarm/Sarm1 is required for activation of an injury-induced axon death pathway". Science 337 (6093): 481–484. July 2012. doi:10.1126/science.1223899. PMID 22678360. Bibcode: 2012Sci...337..481O. 
  8. ↑ 8.0 8.1 8.2 "Sarm1-mediated axon degeneration requires both SAM and TIR interactions". The Journal of Neuroscience 33 (33): 13569–13580. August 2013. doi:10.1523/JNEUROSCI.1197-13.2013. PMID 23946415. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 "SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration". Neuron 109 (7): 1118–1136.e11. April 2021. doi:10.1016/j.neuron.2021.02.009. PMID 33657413. 
  10. ↑ 10.0 10.1 10.2 "The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1". Nature 588 (7839): 658–663. December 2020. doi:10.1038/s41586-020-2862-z. PMID 33053563. Bibcode: 2020Natur.588..658J. 
  11. ↑ 11.0 11.1 11.2 "Structural basis for SARM1 inhibition and activation under energetic stress". eLife 9. November 2020. doi:10.7554/eLife.62021. PMID 33185189. 
  12. ↑ "NAD+ metabolism and its roles in cellular processes during ageing". Nature Reviews. Molecular Cell Biology 22 (2): 119–141. February 2021. doi:10.1038/s41580-020-00313-x. PMID 33353981. 
  13. ↑ "CRISPR/Cas9-mediated SARM1 knockout and epitope-tagged mice reveal that SARM1 does not regulate nuclear transcription, but is expressed in macrophages". The Journal of Biological Chemistry 297 (6): 101417. December 2021. doi:10.1016/j.jbc.2021.101417. PMID 34793837. 
  14. ↑ "Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP". The Journal of Biological Chemistry 294 (52): 19831–19843. December 2019. doi:10.1074/jbc.REV119.009635. PMID 31672920. 
  15. ↑ 15.0 15.1 "cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons". Experimental Neurology 329: 113252. July 2020. doi:10.1016/j.expneurol.2020.113252. PMID 32087251. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 "A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death". iScience 15: 452–466. May 2019. doi:10.1016/j.isci.2019.05.001. PMID 31128467. Bibcode: 2019iSci...15..452Z. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 "SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites" (in English). iScience 25 (2): 103812. February 2022. doi:10.1016/j.isci.2022.103812. PMID 35198877. Bibcode: 2022iSci...25j3812A. 
  18. ↑ "Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN". The Journal of Cell Biology 221 (2): e202106080. February 2022. doi:10.1083/jcb.202106080. PMID 34935867. 
  19. ↑ "NAD+ cleavage activity by animal and plant TIR domains in cell death pathways". Science 365 (6455): 793–799. August 2019. doi:10.1126/science.aax1911. PMID 31439792. Bibcode: 2019Sci...365..793H. 
  20. ↑ 20.0 20.1 "Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate". eLife 10. May 2021. doi:10.7554/eLife.67381. PMID 33944777. 
  21. ↑ "Initial Kinetic Characterization of Sterile Alpha and Toll/Interleukin Receptor Motif-Containing Protein 1". Biochemistry 59 (8): 933–942. March 2020. doi:10.1021/acs.biochem.9b01078. PMID 32049506. 
  22. ↑ 22.0 22.1 22.2 22.3 "Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules". Molecular Cell 82 (9): 1643–1659.e10. May 2022. doi:10.1016/j.molcel.2022.03.007. PMID 35334231. 
  23. ↑ "Acidic pH irreversibly activates the signaling enzyme SARM1". The FEBS Journal 288 (23): 6783–6794. December 2021. doi:10.1111/febs.16104. PMID 34213829. 
  24. ↑ "Small Molecule SARM1 Inhibitors Recapitulate the SARM1-/- Phenotype and Allow Recovery of a Metastable Pool of Axons Fated to Degenerate". Cell Reports 34 (1): 108588. January 2021. doi:10.1016/j.celrep.2020.108588. PMID 33406435. 
  25. ↑ 25.0 25.1 "Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy". Brain 144 (10): 3226–3238. November 2021. doi:10.1093/brain/awab184. PMID 33964142. 
  26. ↑ "Identification of the first noncompetitive SARM1 inhibitors". Bioorganic & Medicinal Chemistry 28 (18): 115644. September 2020. doi:10.1016/j.bmc.2020.115644. PMID 32828421. 
  27. ↑ 27.0 27.1 27.2 "Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease". Neuron 110 (22): S0896–6273(22)00749–8. September 2022. doi:10.1016/j.neuron.2022.08.017. PMID 36087583. 
  28. ↑ "Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons". Neurobiology of Disease 171: 105808. September 2022. doi:10.1016/j.nbd.2022.105808. PMID 35779777. 
  29. ↑ 29.0 29.1 "The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila". eLife 11: e80245. December 2022. doi:10.7554/eLife.80245. PMID 36476387. 
  30. ↑ 30.0 30.1 "A conformation-specific nanobody targeting the nicotinamide mononucleotide-activated state of SARM1". Nature Communications 13 (1): 7898. December 2022. doi:10.1038/s41467-022-35581-y. PMID 36550129. Bibcode: 2022NatCo..13.7898H. 
  31. ↑ 31.0 31.1 31.2 "Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1". Cell Reports 32 (5): 107999. August 2020. doi:10.1016/j.celrep.2020.107999. PMID 32755591. 
  32. ↑ "Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1". eLife 10: e72823. December 2021. doi:10.7554/eLife.72823. PMID 34870595. 
  33. ↑ "Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss". Cell Reports 37 (3): 109872. October 2021. doi:10.1016/j.celrep.2021.109872. PMID 34686345. 
  34. ↑ "Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection". Experimental Neurology 345: 113842. November 2021. doi:10.1016/j.expneurol.2021.113842. PMID 34403688. 
  35. ↑ "Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapy-induced degeneration". Proceedings of the National Academy of Sciences of the United States of America 115 (42): 10654–10659. October 2018. doi:10.1073/pnas.1809392115. PMID 30257945. Bibcode: 2018PNAS..11510654L. 
  36. ↑ "Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain". Proceedings of the National Academy of Sciences of the United States of America 119 (35): e2208457119. August 2022. doi:10.1073/pnas.2208457119. PMID 35994671. Bibcode: 2022PNAS..11908457F. 
  37. ↑ "MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2". eLife 6. January 2017. doi:10.7554/eLife.22540. PMID 28095293. 
  38. ↑ "Palmitoylation enables MAPK-dependent proteostasis of axon survival factors". Proceedings of the National Academy of Sciences of the United States of America 115 (37): E8746–E8754. September 2018. doi:10.1073/pnas.1806933115. PMID 30150401. Bibcode: 2018PNAS..115E8746S. 
  39. ↑ "DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration". Molecular Neurobiology 57 (2): 1146–1158. February 2020. doi:10.1007/s12035-019-01796-2. PMID 31696428. 
  40. ↑ "Pathological axonal death through a MAPK cascade that triggers a local energy deficit". Cell 160 (1–2): 161–176. January 2015. doi:10.1016/j.cell.2014.11.053. PMID 25594179. 
  41. ↑ "Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1". Brain 139 (Pt 4): 1094–1105. April 2016. doi:10.1093/brain/aww001. PMID 26912636. 
  42. ↑ "Primary Traumatic Axonopathy in Mice Subjected to Impact Acceleration: A Reappraisal of Pathology and Mechanisms with High-Resolution Anatomical Methods". The Journal of Neuroscience 38 (16): 4031–4047. April 2018. doi:10.1523/JNEUROSCI.2343-17.2018. PMID 29567804. 
  43. ↑ "Sarm1 deletion reduces axon damage, demyelination, and white matter atrophy after experimental traumatic brain injury". Experimental Neurology 321: 113040. November 2019. doi:10.1016/j.expneurol.2019.113040. PMID 31445042. 
  44. ↑ "Sarm1 loss reduces axonal damage and improves cognitive outcome after repetitive mild closed head injury". Experimental Neurology 327: 113207. May 2020. doi:10.1016/j.expneurol.2020.113207. PMID 31962129. 
  45. ↑ "Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures". Acta Neuropathologica Communications 9 (1): 89. May 2021. doi:10.1186/s40478-021-01193-8. PMID 34001261. 
  46. ↑ "Traumatic axonopathy in spinal tracts after impact acceleration head injury: Ultrastructural observations and evidence of SARM1-dependent axonal degeneration". Experimental Neurology 359: 114252. October 2022. doi:10.1016/j.expneurol.2022.114252. PMID 36244414. 
  47. ↑ Alexandris, Athanasios S.; Lee, Youngrim; Lehar, Mohamed; Alam, Zahra; McKenney, James; Perdomo, Dianela; Ryu, Jiwon; Welsbie, Derek et al. (2023-03-14). "Traumatic Axonal Injury in the Optic Nerve: The Selective Role of SARM1 in the Evolution of Distal Axonopathy". Journal of Neurotrauma 40 (15–16): 1743–1761. doi:10.1089/neu.2022.0416. ISSN 1557-9042. PMID 36680758. 
  48. ↑ "Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice". Brain 139 (Pt 12): 3092–3108. December 2016. doi:10.1093/brain/aww251. PMID 27797810. 
  49. ↑ "Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program". JCI Insight 4 (17). September 2019. doi:10.1172/jci.insight.129920. PMID 31484833. 
  50. ↑ "Protection against oxaliplatin-induced mechanical and thermal hypersensitivity in Sarm1-/- mice". Experimental Neurology 338: 113607. April 2021. doi:10.1016/j.expneurol.2021.113607. PMID 33460644. https://www.repository.cam.ac.uk/handle/1810/316851. 
  51. ↑ "Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation". Scientific Reports 10 (1): 21889. December 2020. doi:10.1038/s41598-020-78896-w. PMID 33318563. Bibcode: 2020NatSR..1021889C. 
  52. ↑ 52.0 52.1 "Deletion of Sarm1 gene is neuroprotective in two models of peripheral neuropathy". Journal of the Peripheral Nervous System 22 (3): 162–171. September 2017. doi:10.1111/jns.12219. PMID 28485482. 
  53. ↑ "Sarm1 Gene Deficiency Attenuates Diabetic Peripheral Neuropathy in Mice". Diabetes 68 (11): 2120–2130. November 2019. doi:10.2337/db18-1233. PMID 31439642. 
  54. ↑ "Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury". Experimental Eye Research 171: 54–61. June 2018. doi:10.1016/j.exer.2018.03.007. PMID 29526794. 
  55. ↑ "SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration". Life Science Alliance 3 (5): e201900618. May 2020. doi:10.26508/lsa.201900618. PMID 32312889. 
  56. ↑ "SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration". The Journal of Cell Biology 219 (8): e201912047. August 2020. doi:10.1083/jcb.201912047. PMID 32609299. 
  57. ↑ "SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration". eLife 9: e62027. October 2020. doi:10.7554/eLife.62027. PMID 33107823. 
  58. ↑ "SARM1 Ablation Is Protective and Preserves Spatial Vision in an In Vivo Mouse Model of Retinal Ganglion Cell Degeneration". International Journal of Molecular Sciences 23 (3): 1606. January 2022. doi:10.3390/ijms23031606. PMID 35163535. 
  59. ↑ "SARM1 Promotes Photoreceptor Degeneration in an Oxidative Stress Model of Retinal Degeneration". Frontiers in Neuroscience 16: 852114. 2022. doi:10.3389/fnins.2022.852114. PMID 35431772. 
  60. ↑ Liu, Pingting; Chen, Wei; Jiang, Haowen; Huang, Haoliang; Liu, Liping; Fang, Fang; Li, Liang; Feng, Xue et al. (2023-06-13). "Differential effects of SARM1 inhibition in traumatic glaucoma and EAE optic neuropathies". Molecular Therapy. Nucleic Acids 32: 13–27. doi:10.1016/j.omtn.2023.02.029. ISSN 2162-2531. PMID 36950280. 
  61. ↑ "Systemic loss of Sarm1 protects Schwann cells from chemotoxicity by delaying axon degeneration". Communications Biology 3 (1): 49. January 2020. doi:10.1038/s42003-020-0776-9. PMID 32001778. 
  62. ↑ "A SARM1/mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model". The Journal of Clinical Investigation 132 (23): e161566. October 2022. doi:10.1172/JCI161566. PMID 36287202. 
  63. ↑ Montoro-Gámez, Carolina; Nolte, Hendrik; Molinié, Thibaut; Evangelista, Giovanna; Tröder, Simon; Barth, Esther; Popovic, Milica; Trifunovic, Aleksandra et al. (2023-04-22). "SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency". Brain: A Journal of Neurology 146 (10): 4117–4131. doi:10.1093/brain/awad136. ISSN 1460-2156. PMID 37086482. https://pubmed.ncbi.nlm.nih.gov/37086482. 
  64. ↑ "Natural variants of human SARM1 cause both intrinsic and dominant loss-of-function influencing axon survival". Scientific Reports 12 (1): 13846. August 2022. doi:10.1038/s41598-022-18052-8. PMID 35974060. Bibcode: 2022NatSR..1213846A. 
  65. ↑ "Severe biallelic loss-of-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence". Experimental Neurology 320: 112961. October 2019. doi:10.1016/j.expneurol.2019.112961. PMID 31136762. 
  66. ↑ "Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia". Experimental Neurology 320: 112958. October 2019. doi:10.1016/j.expneurol.2019.112958. PMID 31132363. https://www.biorxiv.org/content/10.1101/610907v1. 
  67. ↑ "Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders". eLife 10: e70905. November 2021. doi:10.7554/eLife.70905. PMID 34796871. 
  68. ↑ "Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients". Molecular Neurodegeneration 17 (1): 1. January 2022. doi:10.1186/s13024-021-00511-x. PMID 34991663. 
  69. ↑ "SARM1 is required in human derived sensory neurons for injury-induced and neurotoxic axon degeneration". Experimental Neurology 339: 113636. May 2021. doi:10.1016/j.expneurol.2021.113636. PMID 33548217. 
  70. ↑ "Structural Evidence for an Octameric Ring Arrangement of SARM1". Journal of Molecular Biology 431 (19): 3591–3605. September 2019. doi:10.1016/j.jmb.2019.06.030. PMID 31278906. 
  71. ↑ "Multiple domain interfaces mediate SARM1 autoinhibition". Proceedings of the National Academy of Sciences of the United States of America 118 (4): e2023151118. January 2021. doi:10.1073/pnas.2023151118. PMID 33468661. Bibcode: 2021PNAS..11823151S. 
  72. ↑ "A duplex structure of SARM1 octamers stabilized by a new inhibitor". Cellular and Molecular Life Sciences 80 (1): 16. December 2022. doi:10.1007/s00018-022-04641-3. PMID 36564647. 
  73. ↑ "Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons". PLOS Biology 8 (1): e1000300. January 2010. doi:10.1371/journal.pbio.1000300. PMID 20126265. 
  74. ↑ "Absence of SARM1 rescues development and survival of NMNAT2-deficient axons". Cell Reports 10 (12): 1974–1981. March 2015. doi:10.1016/j.celrep.2015.02.060. PMID 25818290. 
  75. ↑ "Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration". Science 305 (5686): 1010–1013. August 2004. doi:10.1126/science.1098014. PMID 15310905. Bibcode: 2004Sci...305.1010A. 
  76. ↑ "Nicotinamide mononucleotide adenylyl transferase-mediated axonal protection requires enzymatic activity but not increased levels of neuronal nicotinamide adenine dinucleotide". The Journal of Neuroscience 29 (17): 5525–5535. April 2009. doi:10.1523/JNEUROSCI.5469-08.2009. PMID 19403820. 
  77. ↑ "Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo". The Journal of Neuroscience 29 (20): 6526–6534. May 2009. doi:10.1523/JNEUROSCI.1429-09.2009. PMID 19458223. 
  78. ↑ "Axonal degeneration is blocked by nicotinamide mononucleotide adenylyltransferase (Nmnat) protein transduction into transected axons". The Journal of Biological Chemistry 285 (53): 41211–41215. December 2010. doi:10.1074/jbc.C110.193904. PMID 21071441. 
  79. ↑ "NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion". eLife 5. October 2016. doi:10.7554/eLife.19749. PMID 27735788. 
  80. ↑ "An 85-kb tandem triplication in the slow Wallerian degeneration (Wlds) mouse". Proceedings of the National Academy of Sciences of the United States of America 95 (17): 9985–9990. August 1998. doi:10.1073/pnas.95.17.9985. PMID 9707587. Bibcode: 1998PNAS...95.9985C. 
  81. ↑ "Non-nuclear Wld(S) determines its neuroprotective efficacy for axons and synapses in vivo". The Journal of Neuroscience 29 (3): 653–668. January 2009. doi:10.1523/JNEUROSCI.3814-08.2009. PMID 19158292. 
  82. ↑ "Wld S protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice". The Journal of Cell Biology 184 (4): 491–500. February 2009. doi:10.1083/jcb.200807175. PMID 19237596. 
  83. ↑ "Targeting NMNAT1 to axons and synapses transforms its neuroprotective potency in vivo". The Journal of Neuroscience 30 (40): 13291–13304. October 2010. doi:10.1523/JNEUROSCI.1189-10.2010. PMID 20926655. 
  84. ↑ "A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration". Cell Death and Differentiation 22 (5): 731–742. May 2015. doi:10.1038/cdd.2014.164. PMID 25323584. 
  85. ↑ "Wallerian Degeneration Is Executed by an NMN-SARM1-Dependent Late Ca(2+) Influx but Only Modestly Influenced by Mitochondria". Cell Reports 13 (11): 2539–2552. December 2015. doi:10.1016/j.celrep.2015.11.032. PMID 26686637. 
  86. ↑ 86.0 86.1 "SARM1 activation triggers axon degeneration locally via NAD⁺ destruction". Science 348 (6233): 453–457. April 2015. doi:10.1126/science.1258366. PMID 25908823. Bibcode: 2015Sci...348..453G. 
  87. ↑ "Live imaging reveals the cellular events downstream of SARM1 activation". eLife 10: e71148. November 2021. doi:10.7554/eLife.71148. PMID 34779400. 
  88. ↑ "Macrophage depletion blocks congenital SARM1-dependent neuropathy". The Journal of Clinical Investigation 132 (23): e159800. October 2022. doi:10.1172/JCI159800. PMID 36287209. 
  89. ↑ "NMNAT2 in cortical glutamatergic neurons exerts both cell and non-cell autonomous influences to shape cortical development and to maintain neuronal health". bioRxiv: 2022.02.05.479195. 2022-02-08. doi:10.1101/2022.02.05.479195. 

External links

  • SARM1 (Wikigenes collaborative publishing)



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