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Implication of folate deficiency in CYP2U1 loss of function

Claire Pujol 1, 2, * Anne Legrand 3 Livia Parodi 1 Priscilla Thomas 1, 2 Fanny Mochel 1 Dario Saracino 1 Giulia Coarelli 1 Marijana Croon 4 Milica Popovic 4 Manon Valet 5 Nicolas Villain 6, 7 Shahira Elshafie 8 Mahmoud Issa 9 Stephane Zuily 10 Mathilde Renaud 11, 12 Cécilia Marelli-Tosi 13 Marine Legendre 14, 15 Aurélien Trimouille 14, 15 Isabelle Kemlin 16 Sophie Mathieu 16 Joseph G. Gleeson 17 Foudil Lamari 18 Daniele Galatolo 19 Rana Alkouri 18 Chantal Tse 18 Diana Rodriguez 16 Claire Ewenczyk 1 Florence Fellmann 20 Thierry Kuntzer 20 Emilie Blond 21 Khalid H. El Hachimi 1, 22 Frédéric Darios 1 Alexandre Seyer 23 Anastasia D. Gazi 2 Patrick Giavalisco 24 Silvina Perin 24 Jean-Luc Boucher 25 Laurent Le Corre 25 Filippo M. Santorelli 26 Cyril Goizet 14, 15 Maha S. Zaki 9 Serge Picaud 5 Arnaud Mourier 27 Sophie Steculorum 28 Cyril Mignot 29 Alexandra Durr 1 Aleksandra Trifunovic 4 Giovanni Stevanin 1, 22, * 
* Corresponding author
Abstract : 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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Submitted on : Monday, September 20, 2021 - 4:32:18 PM
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Claire Pujol, Anne Legrand, Livia Parodi, Priscilla Thomas, Fanny Mochel, et al.. Implication of folate deficiency in CYP2U1 loss of function. Journal of Experimental Medicine, Rockefeller University Press, 2021, 218 (11), pp.e20210846. ⟨10.1084/jem.20210846⟩. ⟨pasteur-03349041⟩



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