Implication of folate deficiency in CYP2U1 loss of function
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.
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