SIRT1 activation rescues the mislocalization of RNA-binding proteins and cognitive defects induced by inherited cobalamin disorders

Ghemrawi, Rose; Arnold, Carole; Battaglia-Hsu, Shyue-Fang; Pourié, Grégory; Trinh, Isabelle; Bassila, Christine; Rashka, Charif; Wiedemann, Arnaud; Flayac, Justine; Robert, Aurélie; Dreumont, Natacha; Feillet, François; Guéant, Jean‐Louis; Coelho, David

doi:10.1016/j.metabol.2019.153992

Cited by 23 publications

(31 citation statements)

References 38 publications

(47 reference statements)

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“…Methionine, folate, or B12 deprivation reduces cell proliferation due to blocks in cell cycling [ 38 , 39 , 40 , 41 ], and deficiencies in one of these metabolites, either through deprivation or genetic alterations, has been shown to cause global DNA hypomethylation [ 41 , 42 , 43 , 44 ]. Methionine deprivation can cause a global decrease in histone methylation [ 41 , 45 ] and models of B12 deficiency have also been shown to decrease the methylation level of proteins [ 46 , 47 ] ( Figure 2 A).…”

Section: Methionine Folate and B12 Deficiency On One-carbon Metamentioning

confidence: 99%

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

et al. 2020

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Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.

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Section: Methionine Folate and B12 Deficiency On One-carbon Metamentioning

confidence: 99%

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

et al. 2020

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“…The subcellular mislocalization of RNA binding proteins (RBP) observed in transgenic mouse and cell models and patient fibroblasts with impaired cellular availability of Cbl led to subsequent global dysregulation of mRNA trafficking and dramatic transcriptomic changes related to metabolic processing of RNA, cellular response to stress, regulation of cell cycle, neurogenesis and neuron differentiation, plasticity and development [7,8]. These results suggested that transcriptomic dysregulation could be an important contributor to the pathogenesis of the inherited disorders of Cbl metabolism through mechanisms that remain to be dissected.…”

Section: Introductionmentioning

confidence: 99%

Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing

Rashka

Hergalant

Dreumont

et al. 2020

Human Molecular Genetics

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ABSTRACT Vitamin B12 or cobalamin (Cbl) metabolism can be affected by genetic defects leading to defective activity of either methylmalonyl-CoA mutase or methionine synthase or both enzymes. Patients usually present with a wide spectrum of pathologies suggesting that various cellular processes could be affected by modifications in gene expression. We have previously demonstrated that these genetic defects are associated with subcellular mislocalization of RNA-binding proteins (RBP) and subsequent altered nucleo-cytoplasmic shuttling of mRNAs. In order to characterize the possible changes of gene expression in these diseases, we have investigated global gene expression in fibroblasts from patients with cblC and cblG inherited disorders by RNA-seq. The most differentially expressed genes are strongly associated with developmental processes, neurological, ophthalmologic and cardiovascular diseases. These associations are consistent with the clinical presentation of cblC and cblG disorders. Multivariate analysis of transcript processing revaled splicing alterations that led to dramatic changes in cytoskeleton organization, response to stress, methylation of macromolecules and RNA binding. The RNA motifs associated with this differential splicing reflected a potential role of RBP such as HuR and HNRNPL. Proteomic analysis confirmed that mRNA processing was significantly disturbed. This study reports a dramatic alteration of gene expression in fibroblasts of patients with cblC and cblG disorders, which resulted partly from disturbed function of RBP. These data suggest to evaluate the rescue of the mislocalization of RBP as a potential strategy in the treatment of severe cases who are resistant to classical treatments with co-enzyme supplements.

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“…Conversely, overexpression of Sirt1 and HSF1 and activation of Sirt1 by SRT1720 as well as addition of vitamin B12 induce a dramatic decrease of ER stress in NIE115 neuronal cells with impaired cellular B12 availability [ 93 ]. Similarly, ER stress is increased in fibroblasts of cblC, cblG and cblG* patients with inherited disorders of cellular vitamin B12 metabolism [ 100 ]. Some of the molecular mechanisms that underlie the neurological manifestations of patients with inherited disorders of vitamin B12 metabolism are related to transcriptomic changes of genes involved in RNA metabolism and ER stress.…”

Section: Introductionmentioning

confidence: 99%

“…The decreased interaction of ELAVL1/HuR with the CRM1/exportin protein of the nuclear pore complex and its subsequent mislocalization result from hypomethylation by decreased SAM and protein methyl transferase CARM1 and dephosphorylation by increased protein phosphatase PP2A. The mislocalization of ELAVL1/HuR triggers the decreased expression of Sirt1 deacetylase and other genes involved in brain development, neuroplasticity, myelin formation and brain aging [ 81 , 100 ]. In summary, Sirt1 plays a prominent role in the pathomechanisms produced by MDD through its role on the acetylation of PGC1α, the transcription of HSP and the subcellular localization of RNA binding proteins (RBP).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, Sirt1 activation by SRT1720 partially restored the methylation and phosphorylation of these RBPs in patients’ fibroblasts. Interestingly, SRT1720, vitamin B12 and SAM treatment improved cognitive functions in conditional MTR -KO mice with brain specific invalidation of Mtr gene encoding MS enzyme [ 100 ]. In particular, SRT1720 improved the deficient hippocampo-dependent learning ability of the mice.…”

Section: Introductionmentioning

confidence: 99%

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Sirt1-PPARS Cross-Talk in Complex Metabolic Diseases and Inherited Disorders of the One Carbon Metabolism

Kosgei

Coelho

Guéant-Rodríguez

et al. 2020

Cells

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Sirtuin1 (Sirt1) has a NAD (+) binding domain and modulates the acetylation status of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and Fork Head Box O1 transcription factor (Foxo1) according to the nutritional status. Sirt1 is decreased in obese patients and increased in weight loss. Its decreased expression explains part of the pathomechanisms of the metabolic syndrome, diabetes mellitus type 2 (DT2), cardiovascular diseases and nonalcoholic liver disease. Sirt1 plays an important role in the differentiation of adipocytes and in insulin signaling regulated by Foxo1 and phosphatidylinositol 3′-kinase (PI3K) signaling. Its overexpression attenuates inflammation and macrophage infiltration induced by a high fat diet. Its decreased expression plays a prominent role in the heart, liver and brain of rat as manifestations of fetal programming produced by deficit in vitamin B12 and folate during pregnancy and lactation through imbalanced methylation/acetylation of PGC1α and altered expression and methylation of nuclear receptors. The decreased expression of Sirt1 produced by impaired cellular availability of vitamin B12 results from endoplasmic reticulum stress through subcellular mislocalization of ELAVL1/HuR protein that shuttles Sirt1 mRNA between the nucleus and cytoplasm. Preclinical and clinical studies of Sirt1 agonists have produced contrasted results in the treatment of the metabolic syndrome. A preclinical study has produced promising results in the treatment of inherited disorders of vitamin B12 metabolism.

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SIRT1 activation rescues the mislocalization of RNA-binding proteins and cognitive defects induced by inherited cobalamin disorders

Cited by 23 publications

References 38 publications

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing

Sirt1-PPARS Cross-Talk in Complex Metabolic Diseases and Inherited Disorders of the One Carbon Metabolism

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