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SIRT1 activation rescues the mislocalization of RNA-binding proteins and cognitive defects induced by inherited
Rose Ghemrawi1, Carole Arnold1, Shyue-Fang Battaglia-Hsu1
1Université de Lorraine, Inserm, UMRS 1256, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, F-54000 Nancy, France.
Background:
The molecular consequences of inborn errors of vitamin B12 or cobalamin metabolism are far from being understood. Moreover, innovative therapeutic strategies are needed for the treatment of neurological outcomes that are usually resistant to conventional treatments. Our previous findings suggest a link between SIRT1, cellular stress and RNA binding proteins (RBP) mislocalization in the pathological mechanisms triggered by impaired vitamin B12 metabolism.
Objectives And Methods:
The goal of this study was to investigate the effects of the pharmacological activation of SIRT1 using SRT1720 on the molecular mechanisms triggered by impaired methionine synthase activity. Experiments were performed in vitro with fibroblasts from patients with the cblG and cblC inherited defects of vitamin B12 metabolism and in vivo with an original transgenic mouse model of methionine synthase deficiency specific to neuronal cells. Subcellular localization of the RBPs HuR, HnRNPA1, RBM10, SRSF1 and Y14 was investigated by immunostaining and confocal microscopy in patient fibroblasts. RBPs methylation and phosphorylation were studied by co-immunoprecipitation and proximity ligation assay. Cognitive performance of the transgenic mice treated with SRT1720 was measured with an aquatic maze.
Results:
Patient fibroblasts with cblC and cblG defects of vitamin B12 metabolism presented with endoplasmic reticulum stress, altered methylation, phosphorylation and subcellular localization of HuR, HnRNPA1 and RBM10, global mRNA mislocalization and increased HnRNPA1-dependent skipping of IRF3 exons. Incubation of fibroblasts with cobalamin, S-adenosyl methionine and okadaic acid rescued the localization of the RBPs and mRNA. The SIRT1 activating compound SRT1720 inhibited ER stress and rescued RBP and mRNA mislocalization and IRF3 splicing. Treatment with this SIRT1 agonist prevented all these hallmarks in patient fibroblasts but it also improved the deficient hippocampo-dependent learning ability of methionine synthase conditional knock-out mice.
Conclusions:
By unraveling the molecular mechanisms triggered by inborn errors of cbl metabolism associating ER stress, RBP mislocalization and mRNA trafficking, our study opens novel therapeutic perspectives for the treatment of inborn errors of vitamin B12 metabolism.
Insights
This study reveals how impaired vitamin B12 metabolism causes cellular stress and RNA binding protein mislocalization. Pharmacological activation of SIRT1 with SRT1720 effectively reverses these molecular defects and improves cognitive function in mice.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Inborn errors of vitamin B12 (cobalamin) metabolism have poorly understood molecular consequences.
- Neurological outcomes in these disorders are often resistant to conventional treatments.
- Previous research suggests a link between SIRT1, cellular stress, and RNA binding protein (RBP) mislocalization in vitamin B12 deficiency.
Purpose of the Study:
- To investigate the effects of SIRT1 pharmacological activation using SRT1720 on molecular mechanisms in impaired methionine synthase activity.
- To explore the impact on RNA binding protein localization and mRNA trafficking in patient-derived cells and a mouse model.
Main Methods:
- Utilized patient fibroblasts with cblC and cblG defects and a transgenic mouse model of methionine synthase deficiency.
- Assessed subcellular localization of RBPs (HuR, HnRNPA1, RBM10, SRSF1, Y14) via immunostaining and confocal microscopy.
- Investigated RBP modifications and cognitive performance in mice treated with the SIRT1 activator SRT1720.
Main Results:
- Patient fibroblasts exhibited endoplasmic reticulum stress, altered RBP methylation/phosphorylation, and mislocalization of RBPs and mRNA.
- Treatment with cobalamin, S-adenosyl methionine, and okadaic acid rescued these molecular defects.
- SRT1720 inhibited ER stress, rescued RBP/mRNA mislocalization and aberrant splicing, and improved cognitive deficits in mice.
Conclusions:
- Unraveled molecular mechanisms linking ER stress, RBP mislocalization, and mRNA trafficking in inborn errors of vitamin B12 metabolism.
- Identified SIRT1 activation as a potential therapeutic strategy for neurological complications associated with these metabolic disorders.
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