Pujol, Claire, Legrand, Anne ORCID: 0000-0001-5703-3493, Parodi, Livia ORCID: 0000-0003-0605-2381, Thomas, Priscilla, Mochel, Fanny, Saracino, Dario ORCID: 0000-0002-4299-9743, Coarelli, Giulia, Croon, Marijana ORCID: 0000-0001-5797-5413, Popovic, Milica ORCID: 0000-0002-8762-6967, Valet, Manon, Villain, Nicolas ORCID: 0000-0002-7429-4289, Elshafie, Shahira ORCID: 0000-0001-5801-0197, Issa, Mahmoud ORCID: 0000-0002-3899-2821, Zuily, Stephane, Renaud, Mathilde, Marelli-Tosi, Cecilia, Legendre, Marine, Trimouille, Aurelien, Kemlin, Isabelle, Mathieu, Sophie, Gleeson, Joseph G., Lamari, Foudil, Galatolo, Daniele ORCID: 0000-0001-9402-2910, Alkouri, Rana, Tse, Chantal, Rodriguez, Diana, Ewenczyk, Claire, Fellmann, Florence, Kuntzer, Thierry, Blond, Emilie, El Hachimi, Khalid H., Darios, Frederic, Seyer, Alexandre, Gazi, Anastasia D., Giavalisco, Patrick, Perin, Silvina, Boucher, Jean-Luc, Le Corre, Laurent, Santorelli, Filippo M., Goizet, Cyril, Zaki, Maha S., Picaud, Serge, Mourier, Arnaud, Steculorum, Sophie Marie, Mignot, Cyril, Durr, Alexandra, Trifunovic, Aleksandra and Stevanin, Giovanni ORCID: 0000-0001-9368-8657 (2021). Implication of folate deficiency in CYP2U1 loss of function. J. Exp. Med., 218 (11). NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-9538

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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-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pujol, ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Legrand, AnneUNSPECIFIEDorcid.org/0000-0001-5703-3493UNSPECIFIED
Parodi, LiviaUNSPECIFIEDorcid.org/0000-0003-0605-2381UNSPECIFIED
Thomas, PriscillaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mochel, FannyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saracino, DarioUNSPECIFIEDorcid.org/0000-0002-4299-9743UNSPECIFIED
Coarelli, GiuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Croon, MarijanaUNSPECIFIEDorcid.org/0000-0001-5797-5413UNSPECIFIED
Popovic, MilicaUNSPECIFIEDorcid.org/0000-0002-8762-6967UNSPECIFIED
Valet, ManonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Villain, NicolasUNSPECIFIEDorcid.org/0000-0002-7429-4289UNSPECIFIED
Elshafie, ShahiraUNSPECIFIEDorcid.org/0000-0001-5801-0197UNSPECIFIED
Issa, MahmoudUNSPECIFIEDorcid.org/0000-0002-3899-2821UNSPECIFIED
Zuily, StephaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renaud, MathildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marelli-Tosi, CeciliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Legendre, MarineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trimouille, AurelienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kemlin, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mathieu, SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gleeson, Joseph G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lamari, FoudilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galatolo, DanieleUNSPECIFIEDorcid.org/0000-0001-9402-2910UNSPECIFIED
Alkouri, RanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tse, ChantalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ewenczyk, ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fellmann, FlorenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuntzer, ThierryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blond, EmilieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
El Hachimi, Khalid H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Darios, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seyer, AlexandreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gazi, Anastasia D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giavalisco, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perin, SilvinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boucher, Jean-LucUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le Corre, LaurentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santorelli, Filippo M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goizet, CyrilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zaki, Maha S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Picaud, SergeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mourier, ArnaudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steculorum, Sophie MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mignot, CyrilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Durr, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trifunovic, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stevanin, GiovanniUNSPECIFIEDorcid.org/0000-0001-9368-8657UNSPECIFIED
URN: urn:nbn:de:hbz:38-606383
DOI: 10.1084/jem.20210846
Journal or Publication Title: J. Exp. Med.
Volume: 218
Number: 11
Date: 2021
Publisher: ROCKEFELLER UNIV PRESS
Place of Publication: NEW YORK
ISSN: 1540-9538
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEREDITARY SPASTIC PARAPLEGIA; AICARDI-GOUTIERES-SYNDROME; CYTOCHROME-P450 2U1; CEREBROSPINAL-FLUID; NEURAL-TUBE; 3D MODEL; MUTATIONS; HYDROXYLATION; EXPRESSION; DISORDERSMultiple languages
Immunology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60638

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