Journal articles

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

1 ICM - Institut du Cerveau = Paris Brain Institute

2 Biologie mitochondriale – Mitochondrial biology

3 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire

4 Universität zu Köln

5 Institut de la Vision

6 Service de Neurologie [CHU Pitié-Salpêtrière]

7 SU - Sorbonne Université

8 Fayoum University

9 National Research Centre - NRC (EGYPT)

10 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique

11 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy

12 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux

13 MMDN - Mécanismes moléculaires dans les démences neurodégénératives

14 CHU Bordeaux [Bordeaux]

15 UB - Université de Bordeaux

16 Service de Neuropédiatrie [CHU Trousseau]

17 UC San Diego - University of California [San Diego]

18 Service de Biochimie Métabolique [CHU Pitié-Salpêtrière]

19 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico

20 UNIL - Université de Lausanne = University of Lausanne

21 HCL - Hospices Civils de Lyon

22 EPHE - École pratique des hautes études

23 Profilomic [Boulogne-Billancourt]

24 Max planck Institute for Biology of Ageing [Cologne]

25 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques

26 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico

27 IBGC - Institut de biochimie et génétique cellulaires

28 Max Planck Institute for Metabolism Research [Cologne, Allemagne]

29 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]

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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Santé publique et épidémiologie

Complete list of metadata

https://hal-pasteur.archives-ouvertes.fr/pasteur-03349041
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Submitted on : Monday, September 20, 2021 - 4:32:18 PM
Last modification on : Tuesday, September 27, 2022 - 4:47:42 AM