Exercise-linked gene Ticam2 emerges as candidate ALS drug target in mice

Voluntary wheel running extended survival in male SOD1G93A mice, a widely used animal model of amyotrophic lateral sclerosis, according to a study published in Cell & Bioscience. Because exercise has been associated in previous work with slower disease progression in ALS, the researchers set out to identify the molecular changes that might underlie this protective effect, focusing on gene activity in the spinal cord.

The team integrated two kinds of transcriptional data: profiles from exercised wild-type mice and gene-expression changes previously linked to ALS in SOD1G93A mice. This cross-analysis revealed 48 genes that overlapped between the exercise-associated and ALS-associated signatures. The overlapping genes were enriched in antiviral and immune-related pathways, including Toll-like receptor signaling, a key arm of the innate immune system.

Among these genes, Ticam2 stood out as a candidate connecting the two transcriptional programs.

To locate where Ticam2 acts, the researchers examined single-cell and single-nucleus transcriptomic datasets. Ticam2 transcripts were found predominantly in microglia, the resident immune cells of the central nervous system.

The single-cell analysis also showed that Ticam2 expression was associated with enhanced Toll-like receptor-related transcriptional activity across disease-associated microglial states. Pseudotime analysis, a computational method that orders cells along an inferred trajectory, revealed distinct distributions of Ticam2-expressing microglial populations along the inferred disease-associated trajectory.

Ticam2 antisense oligonucleotide treatment was associated with a trend toward prolonged survival in SOD1G93A mice. The treatment also significantly increased the number of ChAT-positive motor neurons, a marker used to count surviving motor neurons in the spinal cord.

The authors emphasize that these findings identify Ticam2 as an exercise-responsive, microglia-associated candidate linked to innate immune signaling, and that the results support further investigation of Ticam2 as a potential therapeutic target in ALS. The survival effect of the antisense treatment was reported as a trend rather than a statistically significant prolongation, while the increase in motor neuron counts was significant.

Several caveats frame the work. The survival benefit of exercise was observed in male SOD1G93A mice, and the molecular analysis relied on comparing exercised wild-type mice with ALS-model mice rather than exercising the disease animals directly. The study is also a preprint-style early-release version, subject to further editorial changes before the final version of record.

Even so, the study offers a concrete molecular thread linking a behavioral intervention to a cell type and a signaling pathway implicated in ALS.

Subject of Research: Exercise-associated transcriptomic changes and the microglial gene Ticam2 as a candidate therapeutic target in ALS mouse models

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

Article References: Han, J., Zou, X., Bian, Y., & Wang, H. (2026). Exercise-associated transcriptomic profiling identifies Ticam2 as a candidate therapeutic target in a SOD1G93A mouse model of amyotrophic lateral sclerosis. Cell & Bioscience. https://doi.org/10.1186/s13578-026-01656-2

Image Credits: AI Generated

DOI: 10.1186/s13578-026-01656-2

Keywords: ALS, SOD1G93A mice, Ticam2, microglia, exercise, transcriptomics, Toll-like receptor signaling, antisense oligonucleotide, motor neurons, innate immunity, Exercise-associated, transcriptomic