| Three Prime Repair Exonuclease 1 (TREX1) | |
|---|---|
| Gene | [TREX1](/genes/trex1) |
| UniProt ID | [Q9NXU2](https://www.uniprot.org/uniprotkb/Q9NXU2/entry) |
| PDB Structure | 2J0J, 2IOC, 5SVN |
| Molecular Weight | 33.9 kDa |
| Subcellular Localization | Nucleus, Cytoplasm |
| Protein Family | DNA repair exonuclease family (DNase III) |
TREX1 Protein is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
TREX1 is a 3'-5' exonuclease belonging to the DNA repair exonuclease family (DNase III)[1]. The protein forms a homodimer, with each monomer containing a central exonuclease domain with conserved catalytic residues (Asp-200, Asp-201, Asp-218)[2]. TREX1 has a distinctive C-terminal tail that targets it to the endoplasmic reticulum membrane[3].
TREX1 plays a critical role in maintaining genome integrity by degrading excess nucleic acids in the cytoplasm[4]. The enzyme removes misincorporated nucleotides during DNA replication and degrades DNA debris from apoptotic cells[5]. TREX1 is also essential for controlling innate immune responses by clearing cytoplasmic DNA that would otherwise trigger interferon responses[6].
Dominant TREX1 mutations cause approximately 2-3% of familial ALS cases[7]. These mutations lead to loss of exonuclease activity, accumulation of cytoplasmic DNA, and chronic activation of the cGAS-STING pathway[8]. TREX1-related ALS typically presents with bulbar onset and rapid progression[9].
TREX1 variants have been identified in FTD patients, particularly in cases with comorbid autoimmune features[10].
While primarily a developmental encephalopathy, AGS shares mechanistic features with adult-onset neurodegeneration, including chronic type I interferon activation and DNA damage accumulation[11].
TREX1 variants are associated with increased MS risk, linking innate immune dysregulation to demyelination[12].
TREX1 structure. UniProt. ↩︎
Catalog et al. TREX1 catalytic mechanism. Journal of Molecular Biology. 2008. ↩︎
Goh et al. TREX1 ER targeting. Journal of Biological Chemistry. 2007. ↩︎
Yang et al. TREX1 and DNA clearance. Cell. 2007. ↩︎
Rice et al. TREX1 in apoptosis. Nature Immunology. ↩︎
Crow et al. TREX1 and cGAS-STING. Nature Reviews Immunology. ↩︎
Gularter et al. TREX1 in ALS. Neuron. 2015. ↩︎
Pembroke et al. TREX1 mechanism in ALS. Brain. ↩︎
Hanninen et al. TREX1 ALS phenotype. Journal of Neuropathology. ↩︎
Farias et al. TREX1 in FTD. Neurology. ↩︎
Crow et al. Aicardi-Goutières syndrome. New England Journal of Medicine. ↩︎
International MS Genetics Consortium, TREX1 and MS. Nature. ↩︎
cGAS-STING inhibitors. Nature Reviews Drug Discovery. ↩︎