Implication of folate deficiency in CYP2U1 loss of function

Claire Pujol; Anne Legrand; Livia Parodi; Priscilla Thomas; Fanny Mochel; Dario Saracino; Giulia Coarelli; Marijana Croon; Milica Popovic; Manon Valet; Nicolas Villain; Shahira Elshafie; Mahmoud Issa; Stephane Zuily; Mathilde Renaud; Cécilia Marelli-Tosi; Marine Legendre; Aurélien Trimouille; Isabelle Kemlin; Sophie Mathieu; Joseph G. Gleeson; Foudil Lamari; Daniele Galatolo; Rana Alkouri; Chantal Tse; Diana Rodriguez; Claire Ewenczyk; Florence Fellmann; Thierry Kuntzer; Emilie Blond; Khalid H. El Hachimi; Frédéric Darios; Alexandre Seyer; Anastasia D. Gazi; Patrick Giavalisco; Silvina Perin; Jean-Luc Boucher; Laurent Le Corre; Filippo M. Santorelli; Cyril Goizet; Maha S. Zaki; Serge Picaud; Arnaud Mourier; Sophie Steculorum; Cyril Mignot; Alexandra Durr; Aleksandra Trifunovic; Giovanni Stevanin

doi:10.1084/jem.20210846

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Implication of folate deficiency in CYP2U1 loss of function

Journal article

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Implication of folate deficiency in CYP2U1 loss of function

Claire Pujol, Anne Legrand, Livia Parodi, Priscilla Thomas, Fanny Mochel, Dario Saracino, Giulia Coarelli, Marijana Croon, Milica Popovic, Manon Valet, …

Journal of Experimental Medicine, Vol.218(11)

2021

DOI: https://doi.org/10.1084/jem.20210846

PMID: 34546337

Abstract

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenicmechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, lossof 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 proteomicstudies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels asputative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We alsoconfirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disruptsmitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in ourmouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.

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Title: Implication of folate deficiency in CYP2U1 loss of function
Creators - without role: Claire Pujol - Sorbonne Université
Anne Legrand - Paris Cardiovascular Research Center
Livia Parodi - Sorbonne Université
Priscilla Thomas - Sorbonne Université
Fanny Mochel - Sorbonne Université
Dario Saracino - Sorbonne Université
Giulia Coarelli - Pitié-Salpêtrière Hospital
Marijana Croon - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Milica Popovic - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Manon Valet - Sorbonne Université
Nicolas Villain - Assistance Publique – Hôpitaux de Paris
Shahira Elshafie - Fayoum University
Mahmoud Issa - National Research Centre
Stephane Zuily - Université de Lorraine
Mathilde Renaud - Centre Hospitalier Régional et Universitaire de Nancy
Cécilia Marelli-Tosi - Université de Montpellier, Mécanismes Moléculaires dans les Démences Neurodégénératives - MMDN
Marine Legendre - Centre Hospitalier Universitaire de Bordeaux
Aurélien Trimouille - Centre Hospitalier Universitaire de Bordeaux
Isabelle Kemlin - Sorbonne Université
Sophie Mathieu - Sorbonne Université
Joseph G. Gleeson - University of California, San Diego
Foudil Lamari - Assistance Publique – Hôpitaux de Paris
Daniele Galatolo - Fondazione Stella Maris
Rana Alkouri - Pitié-Salpêtrière Hospital
Chantal Tse - Pitié-Salpêtrière Hospital
Diana Rodriguez - Sorbonne Université
Claire Ewenczyk - Assistance Publique – Hôpitaux de Paris
Florence Fellmann - University of Lausanne
Thierry Kuntzer - University of Lausanne
Emilie Blond - Hospices Civils de Lyon
Khalid H. El Hachimi - Assistance Publique – Hôpitaux de Paris
Frédéric Darios - Pitié-Salpêtrière Hospital
Alexandre Seyer - Profilomic [Boulogne-Billancourt]
Anastasia D. Gazi - Institut Pasteur
Patrick Giavalisco - Max Planck Institute for Biology of Ageing
Silvina Perin - Max Planck Institute for Biology of Ageing
Jean-Luc Boucher - Laboratoire de Chimie
Laurent Le Corre - Université Paris Cité
Filippo M. Santorelli - Fondazione Stella Maris
Cyril Goizet - Centre Hospitalier Universitaire de Bordeaux
Maha S. Zaki - National Research Centre
Serge Picaud - Sorbonne Université
Arnaud Mourier - Institut de Biochimie et Génétique Cellulaires
Sophie Steculorum - Max Planck Institute for Metabolism Research
Cyril Mignot - Assistance Publique – Hôpitaux de Paris
Alexandra Durr - Assistance Publique – Hôpitaux de Paris
Aleksandra Trifunovic - Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Giovanni Stevanin - Sorbonne Université
Publication Details: Journal of Experimental Medicine, Vol.218(11)
Grant note: The Core is supported by “Investissements d’avenir” (ANR-10-IAIHU-06 and ANR-11-INBS-0011-NeurATRIS) and the “Fondation pour la Recherche Medicale. This study was supported financially by the Association Strümpell-Lorrain–Hereditary Spastic Paraplegia patient association (to C. Pujol and G. Stevanin), the Tom Wahlig–Stiftung Foundation (to K.H. El Hachimi and G. Stevanin), the EMBO short-term fellowship (C. Pujol), French state funds through the Agence Nationale de la Recherche under the framework programme Investissements d’Avenir (ANR-10-INBS-07 PHENOMIN), and the European Union through an internal call under the Seventh Framework Programme (NEUROMICS, to G. Stevanin).
Identifiers: 9936753809311
Academic Unit: Mécanismes Moléculaires dans les Démences Neurodégénératives - MMDN
Language: English
Resource Type: Journal article
Local Fields: pasteur-03349041