SARM1

Last updated
SARM1
Identifiers
Aliases SARM1 , MyD88-5, SAMD2, SARM, sterile alpha and TIR motif containing 1, hHsTIR
External IDs OMIM: 607732 MGI: 2136419 HomoloGene: 9015 GeneCards: SARM1
Orthologs
SpeciesHumanMouse
Entrez

23098

237868

Ensembl

ENSG00000004139

ENSMUSG00000050132

UniProt

Q6SZW1
Q0D2N8

Q6PDS3

RefSeq (mRNA)

NM_015077

NM_001168521
NM_172795

RefSeq (protein)

NP_055892
NP_055892.2

NP_001161993
NP_766383

Location (UCSC) Chr 17: 28.36 – 28.4 Mb Chr 11: 78.36 – 78.39 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] SARM1's TIR domain has intrinsic NADase enzymatic activity that is highly conserved from archaea, plants, nematode worms, fruit flies, and humans. [7] [8] [9] In mammals, SARM1 is highly expressed in neurons, where it resides in both cell bodies and axons, and can be associated with mitochondria. [10]

Contents

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. [5] [11] [12] [13] [14] [15] 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. [16] [17] By generating cADPR or NAADP, SARM1 may function as a Ca2+-signaling enzyme similar to CD38. [18] [19] [20] [21] [22]

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. [6] [8] [23] [20] [24] [21] [25] For NAD+, The transglycosidation (base exchange) activity of SARM1 extends beyond simple pyridines and includes many heterocyclic nucleophilic bases. [26]

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. [6] [21] [27] Non-endogenous small chemical molecules have also been shown to inhibit SARM1's enzymatic activity at or near the orthosteric site. [26] [28] [29] [30] [31]

In addition, SARM1's enzymatic activity can be regulated by its allosteric site at the ARM domain, which can bind to NMN or NAD+. [13] [26] The ratio of NMN/NAD+ in cells determines SARM1's enzymatic activity. [13] [21] [32] [33] [34] A chemically-modified cell permeable version of NMN, CZ-48, likely activates SARM1 via interacting with this allosteric region. [20] [35] 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. [36] [37] When NAD+ levels are low, nicotinic acid mononucleotide (NaMN) can bind to the allosteric region and inhibit SARM1 activity, [38] thus explaining the potent axon protection provided by treating neurons with the NaMN precursor nicotinic acid riboside (NaR) while inhibiting NAMPT. [39] Chemical screening approaches have also identified covalent inhibitors of SARM1's allosteric ARM domain region. [24] [40]

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. [41] [42] [43] SARM1 activation also triggers the MAP kinase cascade, indicating some form of feedback loop may exist. [44]

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, [45] [46] [47] [48] [49] [31] [50] [51] chemotherapy-induced neuropathy, [52] [53] [54] [29] [55] [56] [31] diabetic neuropathy, [56] [57] degenerative eye conditions, [58] [59] [60] [61] [62] [63] [64] drug-induced Schwann cell death, [65] Charcot-Marie-Tooth disease, [66] and hereditary spastic paraplegia. [67]

Loss-of-function alleles of the SARM1 gene also occur naturally in the human population, potentially altering susceptibility to various neurological conditions. [68]

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 [69] and childhood-onset polyneuropathy with erythromelalgia. [70] 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). [71] [72]

Wallerian degeneration pathway

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, [11] 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). [11] [12] Loss of SARM1 in human iPSC-derived neurons is also axon protective. [73]

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. [12] The functional unit of SARM1 is an octameric ring. [74] 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. [75] [35] [15] [14] [13] [76]

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. [77] 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. [78] 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. [79] [80] [81] [82] [83] [84] [85] [86] [87] 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. [88] [89] Further studies revealed that NMN could activate SARM1's enzymatic activity. [20] [35] 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+. [13] 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, [13] [14] [15] 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. [13] [26] [33] [34]

SARM1 activation locally triggers a rapid collapse of NAD+ levels in the distal section of the injured axon, which then undergoes degeneration. [90] This collapse in NAD+ levels was later shown to be due to SARM1's TIR domain having intrinsic NAD+ cleavage activity. [6] 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. [6] [19] [20] [21] Activation of SARM1's NADase activity is necessary and sufficient to collapse NAD+ levels and initiate the Wallerian degeneration pathway. [90] [6] 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. [91]

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. [92] [93] [ unreliable source ]

Related Research Articles

<span class="mw-page-title-main">Axon</span> Long projection on a neuron that conducts signals to other neurons

An axon or nerve fiber is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

<span class="mw-page-title-main">Charcot–Marie–Tooth disease</span> Neuromuscular disease

Charcot–Marie–Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most commonly inherited neurological disorder, affecting about one in 2,500 people. It is named after those who classically described it: the Frenchman Jean-Martin Charcot (1825–1893), his pupil Pierre Marie (1853–1940), and the Briton Howard Henry Tooth (1856–1925).

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

<span class="mw-page-title-main">Wallerian degeneration</span> Biological process of axonal degeneration

Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury degenerates. A related process of dying back or retrograde degeneration known as 'Wallerian-like degeneration' occurs in many neurodegenerative diseases, especially those where axonal transport is impaired such as ALS and Alzheimer's disease. Primary culture studies suggest that a failure to deliver sufficient quantities of the essential axonal protein NMNAT2 is a key initiating event.

<span class="mw-page-title-main">Diffuse axonal injury</span> Medical condition

Diffuse axonal injury (DAI) is a brain injury in which scattered lesions occur over a widespread area in white matter tracts as well as grey matter. DAI is one of the most common and devastating types of traumatic brain injury and is a major cause of unconsciousness and persistent vegetative state after severe head trauma. It occurs in about half of all cases of severe head trauma and may be the primary damage that occurs in concussion. The outcome is frequently coma, with over 90% of patients with severe DAI never regaining consciousness. Those who awaken from the coma often remain significantly impaired.

Neurofilaments (NF) are classed as type IV intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring 10 nm in diameter and many micrometers in length. Together with microtubules (~25 nm) and microfilaments (7 nm), they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. The proteins that form neurofilaments are members of the intermediate filament protein family, which is divided into six types based on their gene organization and protein structure. Types I and II are the keratins which are expressed in epithelia. Type III contains the proteins vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP). Type IV consists of the neurofilament proteins NF-L, NF-M, NF-H and α-internexin. Type V consists of the nuclear lamins, and type VI consists of the protein nestin. The type IV intermediate filament genes all share two unique introns not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive type IV gene.

<span class="mw-page-title-main">CD38</span> Protein-coding gene in the species Homo sapiens

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.

<span class="mw-page-title-main">Cyclic ADP-ribose</span> Chemical compound

Cyclic ADP-ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like cAMP) with two phosphate groups present on 5' OH of the adenosine (like ADP), further connected to another ribose at the 5' position, which, in turn, closes the cycle by glycosidic bonding to the nitrogen 1 (N1) of the same adenine base (whose position N9 has the glycosidic bond to the other ribose). The N1-glycosidic bond to adenine is what distinguishes cADPR from ADP-ribose (ADPR), the non-cyclic analog. cADPR is produced from nicotinamide adenine dinucleotide (NAD+) by ADP-ribosyl cyclases (EC 3.2.2.5) as part of a second messenger system.

Neuroregeneration involves the regrowth or repair of nervous tissues, cells or cell products. Neuroregenerative mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

<span class="mw-page-title-main">MFN2</span> Protein-coding gene in the species Homo sapiens

Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.

<span class="mw-page-title-main">Nicotinamide phosphoribosyltransferase</span> Human protein and coding gene

Nicotinamide phosphoribosyltransferase, formerly known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin for its extracellular form (eNAMPT), is an enzyme that in humans is encoded by the NAMPT gene. The intracellular form of this protein (iNAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway that converts nicotinamide to nicotinamide mononucleotide (NMN) which is responsible for most of the NAD+ formation in mammals. iNAMPT can also catalyze the synthesis of NMN from phosphoribosyl pyrophosphate (PRPP) when ATP is present. eNAMPT has been reported to be a cytokine (PBEF) that activates TLR4, that promotes B cell maturation, and that inhibits neutrophil apoptosis.

<span class="mw-page-title-main">Nicotinamide-nucleotide adenylyltransferase</span>

In enzymology, nicotinamide-nucleotide adenylyltransferase (NMNAT) (EC 2.7.7.1) are enzymes that catalyzes the chemical reaction

<span class="mw-page-title-main">NMNAT1</span> Protein-coding gene in the species Homo sapiens

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is an enzyme that in humans is encoded by the nmnat1 gene. It is a member of the nicotinamide-nucleotide adenylyltransferases (NMNATs) which catalyze nicotinamide adenine dinucleotide (NAD) synthesis.

<span class="mw-page-title-main">NMNAT2</span> Protein-coding gene in the species Homo sapiens

Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an enzyme that in humans is encoded by the NMNAT2 gene.

<span class="mw-page-title-main">NINJ1</span> Protein-coding gene in the species Homo sapiens

Ninjurin-1 is a protein that in humans is encoded by the NINJ1 gene.

Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are caloric restriction mimetic compounds that may be helpful in treating various aging-related diseases.

<span class="mw-page-title-main">Toll-interleukin receptor</span> Intracellular signaling domain

The toll-interleukin-1 receptor (TIR) homology domain is an intracellular signaling domain found in MyD88, SARM1, interleukin-1 receptors, toll receptors and many plant R proteins. It contains three highly conserved regions, and mediates protein-protein interactions between the toll-like receptors (TLRs) and signal-transduction components. TIR-like motifs are also found in plant proteins where they are involved in resistance to disease and in bacteria where they are associated with virulence. When activated, TIR domains recruit cytoplasmic adaptor proteins MyD88 (UniProt Q99836) and TOLLIP (toll-interacting protein, UniProt Q9H0E2). In turn, these associate with various kinases to set off signaling cascades. Some TIR domains have also been found to have intrinsic NAD+ cleavage activity, such as in SARM1. In the case of SARM1, the TIR NADase activity leads to the production of Nam, ADPR and cADPR and the activation of downstream pathways involved in Wallerian degeneration and neuron death.

Members of the very wide interleukin-1 receptor (IL-1R) family are characterized by extracellular immunoglobulin-like domains and intracellular Toll/Interleukin-1R (TIR) domain. It is a group of structurally homologous proteins, conserved throughout the species as it was identified from plants to mammals. Proteins of this family play important role in host defence, injury and stress. There are four main groups of TIR domain-containing proteins in animals; Toll-like receptors, Interleukin-1 receptor (IL-1R), cytosolic adaptor proteins and insect and nematode Toll. Each of these groups is involved mainly in host defence; Toll receptors are also involved in embryogenesis.

Preferential motor reinnervation (PMR) refers to the tendency of a regenerating axon in the peripheral nervous system (PNS) to reinnervate a motor pathway as opposed to a somatosensory pathway. PMR affects how nerves regenerate and reinnervate within the PNS after surgical procedures or traumatic injuries. It is important to understand in order to further develop axonal regrowth surgical techniques. Further research of preferential motor reinnervation will lead to a better understanding of peripheral nervous system function in the human body regarding cell roles and abilities.

<span class="mw-page-title-main">Nicotinamide mononucleotide</span> Chemical compound

Nicotinamide mononucleotide is a nucleotide derived from ribose, nicotinamide, nicotinamide riboside and niacin. In humans, several enzymes use NMN to generate nicotinamide adenine dinucleotide (NADH). In mice, it has been proposed that NMN is absorbed via the small intestine within 10 minutes of oral uptake and converted to nicotinamide adenine dinucleotide (NAD+) through the Slc12a8 transporter. However, this observation has been challenged, and the matter remains unsettled.

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