Early dysregulation of sphingomyelin metabolism in the striatum of Huntington's disease mouse models.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by mutant huntingtin protein, leading to progressive motor, cognitive, and behavioral decline. This study investigates the dysregulation of sphingomyelin (SM) metabolism, the most abundant sphingolipid in cellular membranes, in the striatum of R6/2 and zQ175 HD mouse models. Our findings reveal significant alterations in the expression of SM-metabolizing enzymes and a concomitant accumulation of SM in symptomatic HD mice. Notably, transcriptional dysregulations were detectable at early and even pre-symptomatic stages of the disease, suggesting an active role in disease initiation or early progression. Moreover, administration of THI, a sphingolipid modulator, normalized SM levels in R6/2 mice and led to a selective elevation in the expression of the sphingomyelinase gene Smpd3. These results reinforce the concept that sphingolipid metabolism is a critical and druggable pathway in HD, offering a promising target for novel therapeutic interventions.