Implication of folate deficiency in CYP2U1 loss of function.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 11 2021
01 11 2021
Historique:
received:
20
04
2021
revised:
15
07
2021
accepted:
05
08
2021
entrez:
21
9
2021
pubmed:
22
9
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34546337
pii: 212651
doi: 10.1084/jem.20210846
pmc: PMC8480666
pii:
doi:
Substances chimiques
Biomarkers
0
Folic Acid
935E97BOY8
CYP2U1 protein, human
EC 1.14.14.1
Cytochrome P450 Family 2
EC 1.14.14.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021 Pujol et al.
Déclaration de conflit d'intérêts
Disclosures: F. Darios reports "other" from Dynacure SAS outside the submitted work. D. Galatolo is supported by a grant from Treat SPG56. G. Stevanin reports grants from ASL-HSP association, the Tom-Wahlig-Stiftung Foundation, and the European Union 7th Framework Programme (Neuromics); non-financial support from Agence Nationale de la Recherche (framework programme Investissements d'Avenir) during the conduct of the study; and grants from Biogen outside the submitted work. N. Vilain reports grants from Fondation Bettencourt-Schueller, Fondation Servier, Union Nationale pour les Intérêts de la Médecine, and Fondation pour la Recherche sur l'Alzheimer; non-financial support from Movement Disorders Society, Merz-Pharma, and GE Healthcare SAS; and "other" from Biogen, Eisai, Eli-Lilly, Roche, Janssen - Johnson & Johnson, and Alector outside the submitted work. No other disclosures were reported.
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