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Publication : Implication of folate deficiency in CYP2U1 loss of function.

First Author  Pujol C Year  2021
Journal  J Exp Med Volume  218
Issue  11 PubMed ID  34546337
Mgi Jnum  J:328659 Mgi Id  MGI:6871822
Doi  10.1084/jem.20210846 Citation  Pujol C, et al. (2021) Implication of folate deficiency in CYP2U1 loss of function. J Exp Med 218(11):e20210846
abstractText  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-alpha 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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