SARM1

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]

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 Wld^S 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 Wld^S 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]}

• SARM1 (Wikigenes collaborative publishing)