Implication of folate deficiency in CYP2U1 loss of function

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.

Automated summary

This study characterized a mouse model lacking the Cyp2u1 gene, which partially recapitulated the clinical and biochemical phenotypes of patients with hereditary spastic paraplegias. Through electron microscopy, lipidomic, and proteomic studies, potential biomarkers were identified in mouse models and fluids from patients with CYP2U1 mutations, confirming brain calcifications as a potential marker. The results suggest that CYP2U1 deficiency disrupts mitochondrial function, impacting neurodevelopment and leading to a neurodegenerative process in multiple tissues.