Implication of folate deficiency in CYP2U1 loss of function-Reference-Cited by-同舟云学术

Implication of folate deficiency in CYP2U1 loss of function

Published:2021-09-21 Issue:11 Volume:218 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Pujol Claire¹²^ORCID,Legrand Anne³^ORCID,Parodi Livia¹^ORCID,Thomas Priscilla¹²^ORCID,Mochel Fanny¹^ORCID,Saracino Dario¹^ORCID,Coarelli Giulia¹^ORCID,Croon Marijana⁴^ORCID,Popovic Milica⁴^ORCID,Valet Manon⁵^ORCID,Villain Nicolas⁶^ORCID,Elshafie Shahira⁷^ORCID,Issa Mahmoud⁸^ORCID,Zuily Stephane⁹^ORCID,Renaud Mathilde¹⁰^ORCID,Marelli-Tosi Cécilia¹¹^ORCID,Legendre Marine¹²^ORCID,Trimouille Aurélien¹²^ORCID,Kemlin Isabelle¹³^ORCID,Mathieu Sophie¹³^ORCID,Gleeson Joseph G.¹⁴^ORCID,Lamari Foudil¹⁵^ORCID,Galatolo Daniele¹⁶^ORCID,Alkouri Rana¹⁵^ORCID,Tse Chantal¹⁵^ORCID,Rodriguez Diana¹³^ORCID,Ewenczyk Claire¹^ORCID,Fellmann Florence¹⁷^ORCID,Kuntzer Thierry¹⁸^ORCID,Blond Emilie¹⁹^ORCID,El Hachimi Khalid H.¹²⁰^ORCID,Darios Frédéric¹^ORCID,Seyer Alexandre²¹^ORCID,Gazi Anastasia D.²^ORCID,Giavalisco Patrick²²^ORCID,Perin Silvina²²^ORCID,Boucher Jean-Luc²³^ORCID,Le Corre Laurent²³^ORCID,Santorelli Filippo M.¹⁶^ORCID,Goizet Cyril¹²^ORCID,Zaki Maha S.⁸^ORCID,Picaud Serge⁵^ORCID,Mourier Arnaud²⁴^ORCID,Steculorum Sophie Marie²⁵^ORCID,Mignot Cyril²⁶^ORCID,Durr Alexandra¹^ORCID,Trifunovic Aleksandra⁴^ORCID,Stevanin Giovanni¹²⁰^ORCID

Affiliation:

1. Sorbonne Université, Institut du Cerveau - Paris Brain Institute ICM, Institut national de la santé et de la recherche médicale, Centre national de la recherche scientifique, Assistance Publique – Hôpitaux de Paris, Hôpital de la Pitié Salpêtrière, Départements Médico-Universitaires Neuroscience 6, Paris, France

2. Pasteur Institute, Centre national de la recherche scientifique UMR 3691, Paris, France

3. Paris University, Paris Cardiovascular Research Centre, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares – Institut national de la santé et de la recherche médicale U97, Paris, France

4. Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany

5. Sorbonne University, Institut national de la santé et de la recherche médicale, Centre national de la recherche scientifique, Institut de la Vision, Paris, France

6. Sorbonne University, Assistance Publique – Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Department of Neurology, Paris, France

7. Department of Clinical Pathology, Fayoum University, Fayoum, Egypt

8. Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt

9. University of Lorraine, Institut national de la santé et de la recherche médicale U 1116, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France

10. University of Lorraine, Institut national de la santé et de la recherche médicale U 1256, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France

11. Mécanismes Moléculaires dans les Démences Neurodégénératives, University of Montpellier, École pratique des hautes études, Institut national de la santé et de la recherche médicale, Montpellier, France; Expert Center for Neurogenetic Diseases, Centre Hospitalier Universitaire, Montpellier, France

12. Genetics Department, Centre Hospitalier Universitaire de Bordeaux, University of Bordeaux, Bordeaux, France

13. Pediatric Neurology Department, Assistance Publique – Hôpitaux de Paris, Hôpital Armand Trousseau, Groupe Hôpitaux Universitaires Est Parisien, Paris, France

14. Department of Neurosciences, University of California, San Diego, La Jolla, CA

15. Metabolic Biochemistry Department, Pitié-Salpêtrière hospital, Assistance Publique – Hôpitaux de Paris, Sorbonne University, Paris, France

16. Molecular Medicine, Istituto di Ricovero e Cura a Carattere Scientifico Stella Maris, Pisa, Italy

17. University of Lausanne, Service de Génétique médicale, Lausanne, Switzerland

18. University of Lausanne, Nerve-Muscle Unit, Department of Clinical Neurosciences, Lausanne, Switzerland

19. Department of Biochemistry and Molecular Biology, Hospices Civils de Lyon, Pierre Bénite, France

20. Paris Sciences et Lettres Research University, École pratique des hautes études, Neurogenetics Unit, Paris, France

21. Profilomic SA, Boulogne-Billancourt, France

22. Max Planck Institute for Biology of Ageing, Cologne, Germany

23. Paris Descartes University, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Centre national de la recherche scientifique UMR 8601, Paris, France

24. Bordeaux University, Centre national de la recherche scientifique, Institut de Biochimie et Génétique Cellulaires, UMR 5095, Bordeaux, France

25. Group Neurocircuit and Function, Max Planck Institute for Metabolism Research, Cologne, Germany

26. Genetics and Cytogenetics Department, Centre de Référence Déficiences Intellectuelles de Causes Rares, Assistance Publique – Hôpitaux de Paris, Paris, France

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.

Funder

Association Strümpell-Lorrain–Hereditary Spastic Paraplegia

Tom Wahlig–Stiftung Foundation

EMBO

Agence Nationale de la Recherche

Investissements d’Avenir

European Union Seventh Framework Programme

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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