Pharmacological modulation with the LXR agonist T0901317 attenuates motor pathology in the SOD1^G93A mouse model of...

Dysregulation of cholesterol metabolism and neuroinflammation are critical drivers of Amyotrophic Lateral Sclerosis (ALS) pathology. Liver X receptors (LXRs) are master regulators of cholesterol homeostasis and immune responses. Here, we evaluated the therapeutic potential of chronic pharmacological modulation using the potent synthetic agonist T0901317 (T0) in the hSOD1^G93A mouse model. To assess both long-term functional outcomes and the underlying molecular mechanisms, T0 was administered via two distinct experimental designs. In a longitudinal cohort treated from postnatal day 60 (P60) until the humane endpoint, T0-treated SOD1G93A mice exhibited delayed body weight loss and sustained improvements in neuromuscular strength and motor coordination. Critically, this continuous treatment preserved functional motor unit connectivity, delayed overall clinical progression, and significantly extended median lifespan. While protective in both sexes, the survival benefit was slightly more pronounced in females. Molecular characterization revealed that the early systemic T0 administration successfully engaged canonical LXR targets in the spinal cord, driving a significant transcriptional upregulation of cholesterol efflux pathways and suppressing pro-inflammatory signaling cascades. This response induced a lipid partitioning, evidenced by a significant accumulation of cholesterol esters within the central nervous system, potentially mitigating lipotoxicity. Taken together, these findings demonstrate that T0901317 treatment exerts a significant beneficial effect, highlighting the pharmacological modulation of these lipid and inflammatory networks as a promising therapeutic strategy for ALS.