Gasdermin D is activated but does not drive neurodegeneration in SOD1(G93A) model of ALS: Implications for targeting pyroptosis.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) - the primary executioner of pyroptosis - remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1(G93A) mouse model of ALS. Our results showed robust GSDMD activation in the spinal cords of SOD1(G93A) animals with elevated expression in Iba1+ microglia. To explore its role in disease progression, we bred C57Bl/6 J.SOD1(G93A) mice onto a C57Bl/6NJ.GSDMD-deficient background. In comparing SOD1(G93A); Gsdmd+/+ and SOD1(G93A); Gsdmd-/- mice, we found that Gsdmd loss did not affect disease onset, weight loss, or grip strength decline in either male or female animals. Notably, GSDMD deficiency resulted in a modest but statistically significant increase in mortality in SOD1(G93A) mice. Moreover, GSDMD absence had minimal impact on astrogliosis, microgliosis and motor neuron loss. These findings show that while GSDMD is activated in the ALS mouse model, its loss does not mitigate key ALS behavioral phenotypes, gliosis or motor neuron loss. This study provides insights into the potential therapeutic relevance of targeting pyroptosis and inflammatory pathways in ALS.