Genetic Ablation of Sarm1 Mitigates Disease Acceleration after Traumatic Brain Injury in the SOD1^G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.

Abstract

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. We sought to determine whether repetitive TBI (rTBI) accelerates disease onset and progression in the transgenic SOD1^G93A 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^G93A (n = 19), and SOD1^G93AxSarm1^KO (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. In sham injured SOD1^G93A 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. SARM1-mediated axonal death pathway promotes pathogenesis after TBI in SOD1^G93A mice suggesting that anti-SARM1 therapeutics are a viable approach to preserve neurological function in injury-accelerated G93A-SOD1 ALS. ANN NEUROL 2025;97:963-975.