Exercise-associated transcriptomic profiling identifies Ticam2 as a candidate therapeutic target in a SOD1G93A mouse model of amyotrophic lateral sclerosis

Exercise may slow disease progression in amyotrophic lateral sclerosis (ALS), but the molecular mechanisms underlying its protective effects remain unclear. Here, voluntary wheel running prolonged survival in male SOD1 G93A mice. To identify potentially actionable molecular targets associated with exercise, we integrated spinal cord transcriptomic profiles from exercised wild-type mice with ALS-associated transcriptional changes in SOD1 G93A mice. This analysis identified 48 overlapping genes enriched in antiviral and immune-related pathways, including Toll-like receptor (TLR) signaling, and highlighted Ticam2 as a candidate linking exercise-associated and ALS-associated transcriptional changes. Single-cell and single-nucleus transcriptomic analyses showed that Ticam2 transcripts were predominantly detected in microglia and that Ticam2 expression was associated with enhanced TLR-related transcriptional activity across disease-associated microglial states. Pseudotime analysis further revealed distinct distributions of Ticam2-expressing microglial populations along the inferred disease-associated trajectory. Ticam2_ASO treatment was associated with a trend toward prolonged survival and significantly increased the number of ChAT-positive motor neurons in SOD1 G93A mice. Together, these findings identify Ticam2 as an exercise-responsive, microglia-associated candidate linked to innate immune signaling and support its further investigation as a potential therapeutic target in ALS.