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

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Huntington’s disease (HD) is a fatal neurodegenerative disorder with no effective cure currently available. Over the past few years our research has shown that alterations in sphingolipid metabolism represent a critical determinant in HD pathogenesis. In particular, aberrant metabolism of sphingosin...

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Main Authors: Pepe, Giuseppe (Author) , Capocci, Luca (Author) , Marracino, Federico (Author) , Realini, Natalia (Author) , Lenzi, Paola (Author) , Martinello, Katiuscia (Author) , Bovier, Tiziana Francesca (Author) , Bichell, Terry Jo (Author) , Scarselli, Pamela (Author) , Di Cicco, Clotilde (Author) , Bowman, Aaron B. (Author) , Digilio, Filomena A. (Author) , Fucile, Sergio (Author) , Fornai, Francesco (Author) , Armirotti, Andrea (Author) , Parlato, Rosanna (Author) , Di Pardo, Alba (Author) , Maglione, Vittorio (Author)
Format: Article (Journal)
Language:English
Published: 4 January 2023
In: Molecular therapy
Year: 2023, Volume: 31, Issue: 1, Pages: 282-299
ISSN:1525-0024
DOI:10.1016/j.ymthe.2022.09.004
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ymthe.2022.09.004
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1525001622005585
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Author Notes:Giuseppe Pepe, Luca Capocci, Federico Marracino, Natalia Realini, Paola Lenzi, Katiuscia Martinello, Tiziana Francesca Bovier, Terry Jo Bichell, Pamela Scarselli, Clotilde Di Cicco, Aaron B. Bowman, Filomena A. Digilio, Sergio Fucile, Francesco Fornai, Andrea Armirotti, Rosanna Parlato, Alba Di Pardo, Vittorio Maglione
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Summary:Huntington’s disease (HD) is a fatal neurodegenerative disorder with no effective cure currently available. Over the past few years our research has shown that alterations in sphingolipid metabolism represent a critical determinant in HD pathogenesis. In particular, aberrant metabolism of sphingosine-1-phosphate (S1P) has been reported in multiple disease settings, including human postmortem brains from HD patients. In this study, we investigate the potential therapeutic effect 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 compound evoked the activation of pro-survival pathways, normalized levels of brain-derived neurotrophic factor, preserved white matter integrity, and stimulated synaptic functions in HD mice. Metabolically, THI restored normal levels of hexosylceramides and stimulated the autophagic and lysosomal machinery, facilitating the reduction of nuclear inclusions of both wild-type and mutant huntingtin proteins.
Item Description:Online verfügbar 16. September 2022, Artikelversion 4. Januar 2023
Gesehen am 06.06.2023
Physical Description:Online Resource
ISSN:1525-0024
DOI:10.1016/j.ymthe.2022.09.004

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