Implication of folate deficiency in CYP2U1 loss of function.
Claire PujolAnne LegrandLivia ParodiPriscilla ThomasFanny MochelDario SaracinoGiulia CoarelliMarijana CroonMilica PopovicManon ValetNicolas VillainShahira ElshafieMahmoud Y IssaStéphane ZuilyMathilde RenaudCécilia Marelli-TosiMarine LegendreAurélien TrimouilleIsabelle KemlinSophie MathieuJoseph G GleesonFoudil LamariDaniele GalatoloRana AlkouriChantal TseDiana RodriguezClaire EwenczykFlorence FellmannThierry KuntzerEmilie BlondKhalid Hamid El HachimiFrédéric DariosAlexandre SeyerAnastasia D GaziPatrick GiavaliscoSilvina PerinJean-Luc BoucherLaurent Le CorreFilippo Maria SantorelliCyril GoizetMaha Saad ZakiSerge PicaudArnaud MourierSophie Marie SteculorumMignot CyrilAlexandra DürrAleksandra TrifunovicGiovanni StevaninPublished in: The Journal of experimental medicine (2021)
Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.