Genetic Ablation of Sarm1 Mitigates Disease Acceleration after Traumatic Brain Injury in the SOD1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.

Objective: Approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Epidemiological data have identified traumatic brain injury (TBI) as an exogenous risk factor for ALS; however, the mechanisms by which TBI may worsen SOD1 ALS remain largely undefined.

Methods: We sought to determine whether repetitive TBI (rTBI) accelerates disease onset and progression in the transgenic SOD1 mouse ALS model, and whether loss of the primary regulator of axonal degeneration sterile alpha and TIR motif containing 1 (Sarm1) mitigates the histological and behavioral pathophysiology. We subjected wild-type (n = 23), Sarm1 knockout (KO; n = 17), SOD1 (n = 19), and SOD1xSarm1 (n = 26) mice of both sexes to rTBI or sham surgery at age 64 days (62-68 days). Body weight and ALS-deficit score were serially assessed up to 17 weeks after surgery and histopathology assessed in layer V of the primary motor cortex at the study end point.

Results: In sham injured SOD1 mice, genetic ablation of Sarm1 did not attenuate axonal loss, improve neurological deficits, or survival. The rTBI accelerated onset of G93A-SOD1 ALS, as indicated by accentuated body weight loss, earlier onset of hindlimb tremor, and shortened survival. The rTBI also triggered TDP-43 mislocalization, enhanced axonal and neuronal loss, microgliosis, and astrocytosis. Loss of Sarm1 significantly diminished the impact of rTBI on disease progression and rescued rTBI-associated neuropathology.

Interpretation: SARM1-mediated axonal death pathway promotes pathogenesis after TBI in SOD1 mice suggesting that anti-SARM1 therapeutics are a viable approach to preserve neurological function in injury-accelerated G93A-SOD1 ALS. ANN NEUROL 2025.