I18 Treatment with THI, an inhibitor of sphingosine-1-phosphate lyase (SGPL1), modulates glycosphingolipid metabolism and results therapeutically effective in a mouse model of Huntington’s disease

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 93; no. Suppl 1; p. A91
• Main Authors: Pepe, Giuseppe, Capocci, Luca, Marracino, Federico, Realini, Natalia, Scarselli, Pamela, Cicco, Clotilde Di, Armirotti, Andrea, Parlato, Rosanna, Pardo, Alba Di, Maglione, Vittorio
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 12-09-2022; BMJ Publishing Group LTD
• Subjects: autophagy; Glucosylceramide; Htt inclusions; Huntingtons disease; I: Experimental therapeutics – preclinical; Metabolism; Pathogenesis; R6/2; Therapeutics
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp-2022-ehdn.244

BackgroundOver the past few years our research has shown that alterations in sphingolipid metabolism represent a critical determinant in Huntington’s disease (HD) pathogenesis. In particular, aberrant metabolism of gangliosides and sphingosine-1-phosphate (S1P) has been reported in multiple disease settings including human post-mortem brains from HD patients.AimIn this study, we investigated the potential therapeutic effect of the inhibition of S1P degradative enzyme SGPL1, by the chronic administration of the THI inhibitor.MethodsIn vivo experiments were carried out in both R6/2 mice and WT littermates, starting from 6 weeks of age. THI was dissolved in DMSO, further diluted in saline (vehicle) and daily administered by intraperitoneal (i.p.) injection at dose of 0.1 mg/kg of body weight. Control mice (WT and R6/2) were daily injected with the same volume of vehicle containing DMSO. The potential beneficial effect of treatment on motor performance was assessed by Horizontal Ladder Task and Rotarod tests. Sphingolipidomic was performed by LC/MS-MS.ResultsWe showed that THI mitigated motor dysfunctions in HD mice. The compound evoked the activation of pro-survival pathways, normalized levels of BDNF and preserved white matter integrity in HD mice. Metabolically, THI restored normal levels of hexosylceramides (glucosylceramide) and stimulated the autophagic and lysosomal machinery, facilitating the reduction of nuclear inclusions of both wild type and mutant huntingtin proteins.ConclusionOur findings reinforce the potential role of (glyco)sphingolipid pathways in HD pathogenesis, and their pharmacological targeting for the development of HD therapies.