Treatment with THI, an inhibitor of sphingosine-1-phosphate lyase, modulates glycosphingolipid metabolism and results therapeutically effective in models of disease

Huntington's disease (HD) is a fatal neurodegenerative disor-der with no effective cure currently available. Over the past few years our research has shown that alterations in sphingoli-pid metabolism represent a critical determinant in HD pathogenesis. In particular, aberrant metabolism of sphingo-sine-1-phosphate (S1P) has been reported in multiple disease settings, including human postmortem brains from HD pa-tients. In this study, we investigate the potential therapeutic ef-fect of the inhibition of S1P degradative enzyme SGPL1, by the chronic administration of the 2-acetyl-5-tetrahydroxybutyl imidazole (THI) inhibitor. We show that THI mitigated motor dysfunctions in both mouse and fly models of HD. The com-pound evoked the activation of pro-survival pathways, normal-ized levels of brain-derived neurotrophic factor, preserved white matter integrity, and stimulated synaptic functions in HD mice. Metabolically, THI restored normal levels of hexosyl-ceramides and stimulated the autophagic and lysosomal ma-chinery, facilitating the reduction of nuclear inclusions of both wild-type and mutant huntingtin proteins.

Automated summary

Huntington's disease (HD) is a fatal neurodegenerative disorder with no cure. Abnormal sphingolipid metabolism, particularly sphingosine-1-phosphate (S1P), has been implicated in HD. This study investigated the therapeutic potential of inhibiting the S1P degradative enzyme SGPL1 using the inhibitor 2-acetyl-5-tetrahydroxybutyl imidazole (THI). THI was found to improve motor dysfunctions, activate pro-survival pathways, restore normal metabolite levels, and reduce nuclear inclusions in HD models.