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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. 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. 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. 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. • Defects of cobalamin metabolism lead to mislocalization of RNA binding proteins. • SRT1720 treatment rescued abnormal localization of RNA binding proteins. • SRT1720 treatment improved the cognitive defects observed in a transgenic mouse model. [ABSTRACT FROM AUTHOR]

Objective: Among the 58 million items collected in the Thomson Reuter's Web of Science database, 100 of the most cited papers up to Oct 7, 2014 was presented in Nature journal last year. I offer a tangential view of the most cited papers of medical relevance placed within this top 100. Methods: By scanning the database of 'The Top 100 Papers' presented by van Noorden et al. (Nature, 2014; 514: 550-553), 1 identified 13 papers which had received highest number of citations in all medical disciplines. Results: The highest ranked (rank 17) among these 13 papers, was by Folstein et al. (1975) offering a practical method for grading the cognitive state of patients. It had received 34,532 citations as of October 7, 2014. The lowest ranked (rank 98), authored by Matthews et al. (1985) on insulin resistance and beta cell function. It had received 12,257 citations. Conclusion: The primary reason why these 13 papers had gained the status of most cited medical papers is simple. They had described either a diagnosis/clinical evaluation of diseased states such as Alzheimer's disease, depression, diabetes, cognitive defect or a simplified methodology for measuring a clinically relevant body constituent such as plasma cholesterol. [ABSTRACT FROM AUTHOR]