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Implication of folate deficiency in CYP2U1 loss of function.

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.

SUBMITTER: Pujol C

PROVIDER: S-EPMC8480666 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Implication of folate deficiency in CYP2U1 loss of function.

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

The Journal of experimental medicine 20210921 11

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 vitam ...[more]

PMID: 34546337

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Project description:Short-term folate deficiency has been linked to cognitive defects. Given folate’s role in regulating nucleotide synthesis and DNA and histone methylation, these changes are often linked to altered gene expression. We hypothesize that chronic folate deficiency will induce memory deficits that can be linked to tissue-specific changes in gene expression. This study placed mice on folic acid deficient or replete diets, containing either no source of folate or AIN-93G normal folic acid intake, beginning post-weaning and persisting through the end of adult life at 18 months. Cognitive outcomes were assessed using the novel object test for memory. Changes in hippocampal gene expression were examined by RNA microarray analysis and confirmed by qPCR. qPCR was also use to compare a subset of significant hippocampal genes to potential changes in liver and heart expression. Ontological categories were determined using GeneCodis for genes whose expression significantly changed in the deficient condition. Significantly enriched motifs in the deficient genes were examined using the HOMER bioinformatics analysis tool to identify transcription factors associated with changing genes. Folic acid deficient mice showed significant memory impairment (P<0.05) compared to replete counterparts beginning at 5 mo and persisting through 17 mo. These deficits were associated with 363 significantly downregulated and 101 significantly upregulated genes (P<0.05, fold change > 2) in the deficient condition. Of the 16 genes whose differential hippocampal expression was confirmed by qPCR, none were also differentially regulated in the heart, and only one was differentially regulated in the liver (P<0.05). Significant ontological categories for differential genes included nucleotide regulation, ion channel activity, and MAPK signaling. Two enriched motifs were identified and determined to be associated with MafB and Zfp410 binding sites. These genes and enriched motifs may represent targets for treatment or investigation of memory-related diseases.

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Implication of folate deficiency in CYP2U1 loss of function.

Publications

Implication of folate deficiency in CYP2U1 loss of function.

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