SARM1: A Key Regulator of Axonal Degeneration and Innate Immunity
Comprehensive genomic and functional analysis of the SARM1 gene, its role in neurodegeneration, and therapeutic targeting
Gene Information Card
| Symbol | SARM1 |
|---|---|
| Full Name | Sterile alpha and TIR motif containing 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 17q11.2 |
| NCBI Gene ID | 23098 ncbi.nlm.nih.gov/gene/23098 |
| Ensembl ID | ENSG00000104131 |
| UniProt ID | Q6SZW1 |
| OMIM ID | 607599 |
| HGNC ID | 17059 |
| Aliases | MyD88-5, SARM, FLJ46536, MGC131581 |
Description
SARM1 (sterile alpha and TIR motif containing 1) is a protein-coding gene located on chromosome 17q11.2. It encodes a member of the Toll-like receptor (TLR) adaptor protein family, characterized by sterile alpha motif (SAM) and Toll/interleukin-1 receptor (TIR) domains. SARM1 is a central executioner of axonal degeneration in response to injury and stress, acting via NAD+ depletion through its TIR domain enzymatic activity. It also functions as a negative regulator of TLR signaling in innate immunity. SARM1 is highly expressed in the nervous system and is implicated in neurodegenerative diseases, traumatic brain injury, and peripheral neuropathy.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Peripheral neuropathy (e.g., Charcot-Marie-Tooth disease) | Gain-of-function mutations in SARM1 lead to constitutive activation of the TIR domain, causing excessive NAD+ cleavage and axonal degeneration. | ClinVar, OMIM |
| Amyotrophic lateral sclerosis (ALS) | SARM1 activation contributes to axonal loss in motor neurons; genetic deletion of SARM1 is protective in ALS mouse models. | NCBI Gene, PubMed |
| Traumatic brain injury | SARM1 mediates Wallerian degeneration after axonal injury; SARM1 knockout mice show reduced axonal damage. | NCBI Gene, PubMed |
| Multiple sclerosis | SARM1 expression is upregulated in demyelinating lesions and contributes to axonal degeneration. | PubMed |
| Chemotherapy-induced peripheral neuropathy | SARM1 activation is triggered by chemotherapeutic agents (e.g., vincristine, paclitaxel), leading to axonal degeneration. | PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | High |
| Spinal cord | 10.8 | High |
| Peripheral nerve | 9.2 | High |
| Testis | 3.1 | Medium |
| Lung | 1.5 | Low |
| Liver | 0.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 8.4 | High expression; used for axonal degeneration studies |
| U-87 MG (glioblastoma) | 6.2 | Moderate expression |
| HEK293 (embryonic kidney) | 1.1 | Low endogenous expression; often used for overexpression studies |
| Jurkat (T-cell leukemia) | 0.5 | Very low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.428G>A (p.Arg143Gln) | Missense | Rare | Gain-of-function; associated with peripheral neuropathy |
| c.1550C>T (p.Thr517Met) | Missense | Rare | Likely gain-of-function; reported in ALS |
| c.2269C>T (p.Arg757Cys) | Missense | Rare | Uncertain significance; reported in Charcot-Marie-Tooth disease |
| c.1A>G (p.Met1Val) | Start loss | Rare | Loss-of-function; protective against axonal degeneration |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., start loss, catalytic domain deletions) impair TIR domain NADase activity, blocking axonal degeneration and providing neuroprotection.
Gain of Function (GOF)
Gain-of-function mutations (e.g., p.Arg143Gln, p.Thr517Met) enhance TIR domain enzymatic activity, leading to excessive NAD+ depletion and axonal degeneration, contributing to peripheral neuropathy and ALS.
Dominant Negative (DN)
Dominant-negative mutations have not been well characterized in SARM1; however, overexpression of catalytically inactive SARM1 can inhibit wild-type SARM1 activity in cellular models.
View complete mutation data：
Gene Ontology (GO)
| • NAD+ nucleosidase activity (GO:0050135) | • TIR domain binding (GO:0035877) |
| • protein homodimerization activity (GO:0042803) | • innate immune response (GO:0045087) |
| • negative regulation of MyD88-dependent toll-like receptor signaling pathway (GO:0034123) | • axonal degeneration (GO:0050803) |
| • Wallerian degeneration (GO:0014042) | • apoptotic process (GO:0006915) |
Pathways
• Toll-like receptor signaling pathway (KEGG: hsa04620)
• Wallerian degeneration (Reactome: R-HSA-9623433)
• NAD+ metabolism (Reactome: R-HSA-196854)
• Programmed cell death (Reactome: R-HSA-5357801)
Protein Summary
The SARM1 protein is a 724-amino acid multidomain protein containing N-terminal SAM domains, a central ARM (armadillo) repeat region, and a C-terminal TIR domain. The TIR domain possesses intrinsic NAD+ glycohydrolase (NADase) activity, which upon activation cleaves NAD+ into nicotinamide and ADP-ribose, leading to rapid depletion of axonal NAD+ and subsequent axonal degeneration. SARM1 is normally autoinhibited; injury or stress signals relieve this inhibition, triggering TIR domain dimerization and enzymatic activation. SARM1 also functions as a negative regulator of TLR3 and TLR4 signaling by interacting with TRIF and MyD88. Its expression is highest in the nervous system, and it is considered a promising therapeutic target for neurodegenerative diseases and acute axonal injury.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SARM1 Knockout HEK293 Cell Line | EDC08107 | Human | 23098 | Details Get a Quote |
| SARM1 Knockout HeLa Cell Line | EDJ-KQ20139 | Human | 23098 | Details Get a Quote |
| SARM1 Knockout A-549 Cell Line | EDJ-KQ18800 | Human | 23098 | Details Get a Quote |
| SARM1 Knockout HCT 116 Cell Line | EDJ-KQ72626 | Human | 23098 | Details Get a Quote |
Displaying Records 1 To 4 Of 4 Records
