Publications by authors named "Carine Bossenmeyer-Pourié"

23 Publications

  • Page 1 of 1

Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.

J Neurol 2021 Jan 8. Epub 2021 Jan 8.

Service de Génétique Médicale, Hôpitaux de Brabois, CHRU de Nancy, Rue du Morvan, 54500, Vandoeuvre-lès-Nancy, France.

Background: STUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1 are now considered a frequent cause of cerebellar ataxia.

Objective: We aimed to improve the clinical, radiological, and molecular delineation of SCAR16 and SCA48.

Methods: Retrospective collection of patients with SCAR16 or SCA48 diagnosed in three French genetic centers (Montpellier, Strasbourg and Nancy).

Results: Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia. Additional findings included cognitive decline, dystonia, parkinsonism and swallowing difficulties. The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients. Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features. We described five new pathogenic variations, two previously reported pathogenic variations, and two rare variants of unknown significance in association with STUB1-related disorders. We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48).

Conclusion: Even though differences are observed between the recessive and dominant forms, it appears that a continuum exists between these two entities. While adding new symptoms associated with STUB1 pathogenic variations, we insist on the difficulty of genetic counselling in STUB1-related pathologies. Finally, we underscore the usefulness of DAT-scan as an additional clue for diagnosis.
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http://dx.doi.org/10.1007/s00415-020-10348-xDOI Listing
January 2021

The Stimulation of Neurogenesis Improves the Cognitive Status of Aging Rats Subjected to Gestational and Perinatal Deficiency of B9-12 Vitamins.

Int J Mol Sci 2020 Oct 28;21(21). Epub 2020 Oct 28.

Faculté de Médecine, INSERM 1256/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France.

A deficiency in B-vitamins is known to lead to persistent developmental defects in various organs during early life. The nervous system is particularly affected with functional retardation in infants and young adults. In addition, even if in some cases no damage appears evident in the beginning of life, correlations have been shown between B-vitamin metabolism and neurodegenerative diseases. However, despite the usual treatment based on B-vitamin injections, the neurological outcomes remain poorly rescued in the majority of cases, compared with physiological functions. In this study, we explored whether a neonatal stimulation of neurogenesis could compensate atrophy of specific brain areas such as the hippocampus, in the case of B-vitamin deficiency. Using a physiological mild transient hypoxia within the first 24 h after birth, rat-pups, submitted or not to neonatal B-vitamin deficiency, were followed until 330-days-of-age for their cognitive capacities and their hippocampus status. Our results showed a gender effect since females were more affected than males by the deficiency, showing a persistent low body weight and poor cognitive performance to exit a maze. Nevertheless, the neonatal stimulation of neurogenesis with hypoxia rescued the maze performance during adulthood without modifying physiological markers, such as body weight and circulating homocysteine. Our findings were reinforced by an increase of several markers at 330-days-of-age in hypoxic animals, such as Ammon's Horn 1hippocampus (CA1) thickness and the expression of key actors of synaptic dynamic, such as the NMDA-receptor-1 (NMDAR1) and the post-synaptic-density-95 (PSD-95). We have not focused our conclusion on the neonatal hypoxia as a putative treatment, but we have discussed that, in the case of neurologic retardation associated with a reduced B-vitamin status, stimulation of the latent neurogenesis in infants could ameliorate their quality of life during their lifespan.
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http://dx.doi.org/10.3390/ijms21218008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662762PMC
October 2020

The Fate of Transplanted Olfactory Progenitors Is Conditioned by the Cell Phenotypes of the Receiver Brain Tissue in Cocultures.

Int J Mol Sci 2020 09 30;21(19). Epub 2020 Sep 30.

Inserm UMR1256/NGERE, Faculté de Medecine, 9 Avenue de la Forêt de Haye, Université de Lorraine, F-54000 Nancy, France.

Among the numerous candidates for cell therapy of the central nervous system (CNS), olfactory progenitors (OPs) represent an interesting alternative because they are free of ethical concerns, are easy to collect, and allow autologous transplantation. In the present study, we focused on the optimization of neuron production and maturation. It is known that plated OPs respond to various trophic factors, and we also showed that the use of Nerve Growth Factor (NGF) allowed switching from a 60/40 neuron/glia ratio to an 80/20 one. Nevertheless, in order to focus on the integration of OPs in mature neural circuits, we cocultured OPs in primary cultures obtained from the cortex and hippocampus of newborn mice. When dissociated OPs were plated, they differentiated into both glial and neuronal phenotypes, but we obtained a 1.5-fold higher viability in cortex/OP cocultures than in hippocampus/OP ones. The fate of OPs in cocultures was characterized with different markers such as BrdU, Map-2, and Synapsin, indicating a healthy integration. These results suggest that the integration of transplanted OPs might by affected by trophic factors and the environmental conditions/cell phenotypes of the host tissue. Thus, a model of coculture could provide useful information on key cell events for the use of progenitors in cell therapy.
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http://dx.doi.org/10.3390/ijms21197249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582579PMC
September 2020

Brain Susceptibility to Methyl Donor Deficiency: From Fetal Programming to Aging Outcome in Rats.

Int J Mol Sci 2019 Nov 14;20(22). Epub 2019 Nov 14.

Faculté de médecine, INSERM 1256/University of Lorraine, F-54500 Vandoeuvre-les-Nancy, France.

Deficiencies in methyl donors, folate, and vitamin B12 are known to lead to brain function defects. Fetal development is the most studied but data are also available for such an impact in elderly rats. To compare the functional consequences of nutritional deficiency in young versus adult rats, we monitored behavioral outcomes of cerebellum and hippocampus circuits in the offspring of deficient mother rats and in adult rats fed a deficient diet from 2 to 8 months-of-age. We present data showing that the main deleterious consequences are found in young ages compared to adult ones, in terms of movement coordination and learning abilities. Moreover, we obtained sex and age differences in the deleterious effects on these functions and on neuronal layer integrity in growing young rats, while deficient adults presented only slight functional alterations without tissue damage. Actually, the cerebellum and the hippocampus develop and maturate according to different time lap windows and we demonstrate that a switch to a normal diet can only rescue circuits that present a long permissive window of time, such as the cerebellum, whereas the hippocampus does not. Thus, we argue, as others have, for supplements or fortifications given over a longer time than the developmental period.
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http://dx.doi.org/10.3390/ijms20225692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888628PMC
November 2019

Methyl Donor Deficiency during Gestation and Lactation in the Rat Affects the Expression of Neuropeptides and Related Receptors in the Hypothalamus.

Int J Mol Sci 2019 Oct 14;20(20). Epub 2019 Oct 14.

Inserm U1256, Faculté de Médecine, Université de Lorraine, 9 Avenue de la Forêt de Haye, F-54500 Vandoeuvre-lès-Nancy, France.

The micronutrients vitamins B9 and B12 act as methyl donors in the one-carbon metabolism involved in transmethylation reactions which critically influence epigenetic mechanisms and gene expression. Both vitamins are essential for proper development, and their deficiency during pregnancy has been associated with a wide range of disorders, including persisting growth retardation. Energy homeostasis and feeding are centrally regulated by the hypothalamus which integrates peripheral signals and acts through several orexigenic and anorexigenic mediators. We studied this regulating system in a rat model of methyl donor deficiency during gestation and lactation. At weaning, a predominance of the anorexigenic pathway was observed in deficient pups, with increased plasma peptide YY and increased hypothalamic pro-opiomelanocortin (POMC) mRNA, in line with abnormal leptin, ghrelin, and insulin secretion and/or signaling during critical periods of fetal and/or postnatal development of the hypothalamus. These results suggest that early methyl donor deficiency can affect the development and function of energy balance circuits, resulting in growth and weight deficits. Maternal administration of folic acid (3 mg/kg/day) during the perinatal period tended to rectify peripheral metabolic signaling and central neuropeptide and receptor expression, leading to reduced growth retardation.
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http://dx.doi.org/10.3390/ijms20205097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829491PMC
October 2019

Developmental Impairments in a Rat Model of Methyl Donor Deficiency: Effects of a Late Maternal Supplementation with Folic Acid.

Int J Mol Sci 2019 Feb 23;20(4). Epub 2019 Feb 23.

Université de Lorraine, Inserm U1256, NGERE, Faculté de Médecine, 9 avenue de la Forêt de Haye, F-54500 Vandoeuvre-lès-Nancy, France.

Vitamins B9 (folate) and B12 act as methyl donors in the one-carbon metabolism which influences epigenetic mechanisms. We previously showed that an embryofetal deficiency of vitamins B9 and B12 in the rat increased brain expression of let-7a and miR-34a microRNAs involved in the developmental control of gene expression. This was reversed by the maternal supply with folic acid (3 mg/kg/day) during the last third of gestation, resulting in a significant reduction of associated birth defects. Since the postnatal brain is subject to intensive developmental processes, we tested whether further folate supplementation during lactation could bring additional benefits. Vitamin deficiency resulted in weaned pups (21 days) in growth retardation, delayed ossification, brain atrophy and cognitive deficits, along with unchanged brain level of let-7a and decreased expression of miR-34a and miR-23a. Whereas maternal folic acid supplementation helped restore the levels of affected microRNAs, it led to a reduction of structural and functional defects taking place during the perinatal/postnatal periods, such as learning/memory capacities. Our data suggest that a gestational B-vitamin deficiency could affect the temporal control of the microRNA regulation required for normal development. Moreover, they also point out that the continuation of folate supplementation after birth may help to ameliorate neurological symptoms commonly associated with developmental deficiencies in folate and B12.
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http://dx.doi.org/10.3390/ijms20040973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413039PMC
February 2019

N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia.

J Pathol 2019 07 19;248(3):291-303. Epub 2019 Mar 19.

Inserm U1256, Nutrition-Genetics and Environmental Exposure, Medical Faculty, University Hospital Center, Université de Lorraine, Vandoeuvre-lès-Nancy, France.

The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule-associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19-7 neuroprogenitors lacking folate. Compared with controls, N-homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N-homocysteinylation dissociated tau and MAPs from β-tubulin, and MS analysis showed that it targets lysine residues critical for their binding to β-tubulin. N-homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days-old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy-thiolactone, the substrate of N-homocysteinylation. Experimental inactivation of MARS prevented the N-homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from β-tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N-homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5254DOI Listing
July 2019

Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways.

Mol Neurobiol 2017 09 17;54(7):5017-5033. Epub 2016 Aug 17.

Inserm U954, 9 Avenue de la Forêt de Haye, 54500, Vandoeuvre-lès-Nancy, France.

The micronutrients folate and vitamin B12 are essential for the proper development of the central nervous system, and their deficiency during pregnancy has been associated with a wide range of disorders. They act as methyl donors in the one-carbon metabolism which critically influences epigenetic mechanisms. In order to depict further underlying mechanisms, we investigated the role of let-7 and miR-34, two microRNAs regulated by methylation, on a rat model of maternal deficiency. In several countries, public health policies recommend periconceptional supplementation with folic acid. However, the question about the duration and periodicity of supplementation remains. We therefore tested maternal supply (3 mg/kg/day) during the last third of gestation from embryonic days (E) 13 to 20. Methyl donor deficiency-related developmental disorders at E20, including cerebellar and interhemispheric suture defects and atrophy of selective cerebral layers, were associated with increased brain expression (by 2.5-fold) of let-7a and miR-34a, with subsequent downregulation of their regulatory targets such as Trim71 and Notch signaling partners, respectively. These processes could be reversed by siRNA strategy in differentiating neuroprogenitors lacking folate, with improvement of their morphological characteristics. While folic acid supplementation helped restoring the levels of let-7a and miR-34a and their downstream targets, it led to a reduction of structural and functional defects taking place during the perinatal period. Our data outline the potential role of let-7 and miR-34 and their related signaling pathways in the developmental defects following gestational methyl donor deficiency and support the likely usefulness of late folate supplementation in at risk women.
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http://dx.doi.org/10.1007/s12035-016-0035-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533871PMC
September 2017

Folate- and vitamin B12-deficient diet during gestation and lactation alters cerebellar synapsin expression via impaired influence of estrogen nuclear receptor α.

FASEB J 2015 Sep 27;29(9):3713-25. Epub 2015 May 27.

*Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy

Deficiency in the methyl donors vitamin B12 and folate during pregnancy and postnatal life impairs proper brain development. We studied the consequences of this combined deficiency on cerebellum plasticity in offspring from rat mothers subjected to deficient diet during gestation and lactation and in rat neuroprogenitor cells expressing cerebellum markers. The major proteomic change in cerebellum of 21-d-old deprived females was a 2.2-fold lower expression of synapsins, which was confirmed in neuroprogenitors cultivated in the deficient condition. A pathway analysis suggested that these proteomic changes were related to estrogen receptor α (ER-α)/Src tyrosine kinase. The influence of impaired ER-α pathway was confirmed by abnormal negative geotaxis test at d 19-20 and decreased phsophorylation of synapsins in deprived females treated by ER-α antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP). This effect was consistent with 2-fold decreased expression and methylation of ER-α and subsequent decreased ER-α/PPAR-γ coactivator 1 α (PGC-1α) interaction in deficiency condition. The impaired ER-α pathway led to decreased expression of synapsins through 2-fold decreased EGR-1/Zif-268 transcription factor and to 1.7-fold reduced Src-dependent phosphorylation of synapsins. The treatment of neuroprogenitors with either MPP or PP1 (4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline, 6,7-dimethoxy-N-(4-phenoxyphenyl)-4-quinazolinamine, SKI-1, Src-l1) Src inhibitor produced similar effects. In conclusion, the deficiency during pregnancy and lactation impairs the expression of synapsins through a deregulation of ER-α pathway.
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http://dx.doi.org/10.1096/fj.14-264267DOI Listing
September 2015

Early methyl donor deficiency produces severe gastritis in mothers and offspring through N-homocysteinylation of cytoskeleton proteins, cellular stress, and inflammation.

FASEB J 2013 Jun 11;27(6):2185-97. Epub 2013 Feb 11.

Institut National de la Santé et de la Recherche Médicale, U954, Nutrition, Génétique et Exposition aux Risques Environnementaux, Vandoeuvre, France.

We examined the gastric mucosa structure and inflammatory status in control well-nourished Wistar dams and in Wistar dams deprived of choline, folate, and vitamin B12 during gestation and suckling periods, and in their offspring just before birth and at weaning. In this model of methyl donor deficiency (MDD), structural protein (E-cadherin and actin) N-homocysteinylation was measured through immunoprecipitation and proximity ligation assays. Cellular stress, inflammation, and apoptosis were estimated by the analysis of the NF-κB pathway, and the expression of superoxide dismutase, cyclooxygenase-2, tumor necrosis factor α, caspases 3 and 9, and TUNEL assay. Aberrant gastric mucosa formation and signs of surface layer erosion were detected in MDD fetuses and weanlings. E-cadherin and actin were N-homocysteinylated (+215 and +249% vs. controls, respectively; P<0.001). Expression of β-catenin staining drastically decreased (-98%; P<0.01). NF-κB pathway was activated (+124%; P<0.01). Expressions of all inflammatory factors (+70%; P<0.01), superoxide dismutase (+55%; P<0.01), and caspases (+104%; P<0.01) were markedly increased. These changes were also observed in dams, to a lesser extent. Early MDD induced gastric mucosa injury similar to atrophic gastritis through structural protein N-homocysteinylation, marked inflammation, and apoptosis, despite activation of repair machinery.
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http://dx.doi.org/10.1096/fj.12-224642DOI Listing
June 2013

Non-injurious neonatal hypoxia confers resistance to brain senescence in aged male rats.

PLoS One 2012 16;7(11):e48828. Epub 2012 Nov 16.

Inserm U954, Vandoeuvre-lès-Nancy, France.

Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia (100% N₂, 5 min) on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence). We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus involving activation of Erk1/2 and repression of p38 and death-associated protein (DAP) kinase. At 21 days of age, increased thicknesses and cell densities were recorded in various subregions, with strong synapsin activation. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity, and with increases of their key regulators, i.e. Erk1/2, the transcription factor EGR-1/Zif-268 and Src kinase. Moreover, the significantly higher interactions between PSD-95 scaffolding protein and NMDA receptors measured in the hippocampus of 720-day-old male animals strengthen the conclusion of increased synaptic functional activity and plasticity associated with neonatal hypoxia. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048828PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500249PMC
March 2013

Methyl donor deficiency affects small-intestinal differentiation and barrier function in rats.

Br J Nutr 2013 Feb 16;109(4):667-77. Epub 2012 Jul 16.

Inserm U-954, Molecular and Cellular Pathology in Nutrition, Faculté de Médecine, CHU Nancy, Nancy-Université, 9 avenue de la Forêt de Haye, BP 184, Nancy, 54500 Vandoeuvre, France.

Dietary methyl donors and their genetic determinants are associated with Crohn's disease risk. We investigated whether a methyl-deficient diet (MDD) may affect development and functions of the small intestine in rat pups from dams subjected to the MDD during gestation and lactation. At 1 month before pregnancy, adult females were fed with either a standard food or a diet without vitamin B12, folate and choline. A global wall hypotrophy was observed in the distal small bowel (MDD animals 0·30 mm v. controls 0·58 mm; P< 0·001) with increased crypt apoptosis (3·37 v. 0·4%; P< 0·001), loss of enterocyte differentiation in the villus and a reduction in intestinal alkaline phosphatase production. Cleaved caspase-3 immunostaining (MDD animals 3·37% v. controls 0·4%, P< 0·001) and the Apostain labelling index showed increased crypt apoptosis (3·5 v. 1·4%; P= 0·018). Decreased proliferation was observed in crypts of the proximal small bowel with a reduced number of minichromosome maintenance 6 (MDD animals 52·83% v. controls 83·17%; P= 0·048) and proliferating cell nuclear antigen-positive cells (46·25 v. 59 %; P= 0·05). This lack of enterocyte differentiation in the distal small bowel was associated with an impaired expression of β-catenin and a decreased β-catenin-E-cadherin interaction. The MDD affected the intestinal barrier in the proximal small bowel by decreasing Paneth cell number after immunostaining for lysosyme (MDD animals 8·66% v. controls 21·66%) and by reducing goblet cell number and mucus production after immunostaining for mucin-2 (crypts 8·66 v. 15·33%; villus 7 v. 17%). The MDD has dual effects on the small intestine by producing dramatic effects on enterocyte differentiation and barrier function in rats.
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http://dx.doi.org/10.1017/S0007114512001869DOI Listing
February 2013

Homocysteinylation of neuronal proteins contributes to folate deficiency-associated alterations of differentiation, vesicular transport, and plasticity in hippocampal neuronal cells.

FASEB J 2012 Oct 19;26(10):3980-92. Epub 2012 Jun 19.

Inserm U954, Faculté de Médecine, 9 Avenue de la Forêt de Haye, F-54500 Vandoeuvre-lès-Nancy, France.

Despite the key role in neuronal development of a deficit in the methyl donor folate, little is known on the underlying mechanisms. We therefore studied the consequences of folate deficiency on proliferation, differentiation, and plasticity of the rat H19-7 hippocampal cell line. Folate deficit reduced proliferation (17%) and sensitized cells to differentiation-associated apoptosis (+16%). Decreased production (-58%) of S-adenosylmethionine (the universal substrate for transmethylation reactions) and increased expression of histone deacetylases (HDAC4,6,7) would lead to epigenomic changes that may impair the differentiation process. Cell polarity, vesicular transport, and synaptic plasticity were dramatically affected, with poor neurite outgrowth (-57%). Cell treatment by an HDAC inhibitor (SAHA) led to a noticeable improvement of cell polarity and morphology, with longer processes. Increased homocysteine levels (+55%) consecutive to folate shortage produced homocysteinylation, evidenced by coimmunoprecipitations and mass spectrometry, and aggregation of motor proteins dynein and kinesin, along with functional alterations, as reflected by reduced interactions with partner proteins. Prominent homocysteinylation of key neuronal proteins and subsequent aggregation certainly constitute major adverse effects of folate deficiency, affecting normal development with possible long-lasting consequences.
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http://dx.doi.org/10.1096/fj.12-205757DOI Listing
October 2012

Increased homocysteinemia is associated with beneficial effects on body weight after long-term high-protein, low-fat diet in rats.

Nutrition 2012 Sep 2;28(9):932-6. Epub 2012 May 2.

INSERM, U954, Nutrition, Génétique et Expositions aux Risques Environnementaux, Vandœuvre-les-Nancy, France.

Objective: Diets rich in protein are often used for weight loss in obese patients, but their long-term effects are not fully understood. Homocysteine (Hcy) is considered to be a risk factor for cardiovascular diseases, and its levels are influenced by diet, particularly the protein and fat content. We studied the effect of diets with varying fat/protein content on body weight and composition, food intake, Hcy, B vitamins, leptin, and several pro-inflammatory cytokines.

Methods: For 2 mo, Long-Evans rats were fed either a low protein/high fat (LP), a standard control (C), or a high protein/low fat (HP) diet containing 5, 15, or 40% protein, respectively, and normal carbohydrate content (55% of total energy).

Results: The HP rats ingested 12 to 15% fewer calories (P < 0.001), gained less weight (P < 0.04), and were less fatty (P < 0.01) than the other groups. Plasma Hcy was increased in HP rats compared to C (+23%) and LP (+29%) rats (P < 0.03). It was positively correlated with protein intake (r = 0.386; P < 0.01). No obvious signs of inflammation were observed in any of the groups. Hcy increase was related directly to decrease in plasma folate (r = -0.372; P < 0.02).

Conclusion: These data confirm the beneficial effects of HP diets on body weight but bring attention to the control of folate allowance to limit the adverse effects of elevated Hcy. Ingestion of folate-rich foods or even folate supplementation should be considered when using these HP diets over the long term for weight loss.
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http://dx.doi.org/10.1016/j.nut.2011.12.015DOI Listing
September 2012

Methyl deficient diet aggravates experimental colitis in rats.

J Cell Mol Med 2011 Nov;15(11):2486-97

Inserm U954, Medical faculty and CHU of Nancy, Nancy-Université, Nancy, France.

Inflammatory bowel diseases (IBD) result from complex interactions between environmental and genetic factors. Low blood levels of vitamin B12 and folate and genetic variants of related target enzymes are associated with IBD risk, in population studies. To investigate the underlying mechanisms, we evaluated the effects of a methyl-deficient diet (MDD, folate, vitamin B12 and choline) in an experimental model of colitis induced by dextran sodium sulphate (DSS), in rat pups from dams subjected to the MDD during gestation and lactation. Four groups were considered (n = 12-16 per group): C DSS(-) (control/DSS(-)), D DSS(-) (deficient/DSS(-)), C DSS(+) (control/DSS(+)) and D DSS(+) (deficient/DSS(+)). Changes in apoptosis, oxidant stress and pro-inflammatory pathways were studied within colonic mucosa. In rat pups, the MDD produced a decreased plasma concentration of vitamin B12 and folate and an increased homocysteine (7.8 ± 0.9 versus 22.6 ± 1.2 μmol/l, P < 0.001). The DSS-induced colitis was dramatically more severe in the D DSS(+) group compared with each other group, with no change in superoxide dismutase and glutathione peroxidase activity, but decreased expression of caspase-3 and Bax, and increased Bcl-2 levels. The mRNA levels of tumour necrosis factor (TNF)-α and protein levels of p38, cytosolic phospolipase A2 and cyclooxygenase 2 were significantly increased in the D DSS(+) pups and were accompanied by a decrease in the protein level of tissue inhibitor of metalloproteinases (TIMP)3, a negative regulator of TNF-α. MDD may cause an overexpression of pro-inflammatory pathways, indicating an aggravating effect of folate and/or vitamin B12 deficiency in experimental IBD. These findings suggest paying attention to vitamin B12 and folate deficits, frequently reported in IBD patients.
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http://dx.doi.org/10.1111/j.1582-4934.2010.01252.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822959PMC
November 2011

Association of neuropeptide W, but not obestatin, with energy intake and endocrine status in Zucker rats. A new player in long-term stress-feeding interactions.

Appetite 2010 Oct 17;55(2):319-24. Epub 2010 Jul 17.

INSERM, U954, Nutrition, Génétique et Expositions aux Risques Environnementaux (NUTRIGENEX), Vandoeuvre, France.

The aim of this study was to ascertain the roles of neuropeptide W (NPW) and obestatin in feeding and endocrine regulations and their interactions with leptin, corticosterone, and insulin, three key hormones involved in metabolic homeostasis. Plasma variations were measured in obese hyperphagic Zucker rats either following a one-day fast, or after chronic food restriction (one-third less food than normal for three weeks). Obestatin did not vary by feeding condition, and did not differ between lean and obese rats; it likely does not play any role in feeding regulation. NPW did not vary with one-day fasting, but was higher in obese rats than in lean rats under satiated (+38%) and fasting (+44%; P<0.01) conditions. In chronically food-restricted obese rats that lost about 10% of their initial body weight, NPW decreased by 18% (P<0.02), in parallel with a similar decrease in plasma insulin (P<0.03), and a 10% decrease of plasma leptin (P<0.001). Corticosterone levels in obese rats were much higher than in lean rats, and increased (P<0.0001) after chronic food restriction, but not after a short fast. Prolonged food restriction was therefore stressful for obese rats. Long-term food shortage associated with insulin, leptin and corticosterone changes is then a critical factor for the regulation of NPW. The NPW up-regulation in hyperphagic conditions and its down-regulation in hypophagic conditions, is compatible with an anorexigenic role of this peptide. NPW thus may be one of the regulatory factors involved in the complex long-term interactions between stress and feeding.
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http://dx.doi.org/10.1016/j.appet.2010.07.002DOI Listing
October 2010

Conditioning-like brief neonatal hypoxia improves cognitive function and brain tissue properties with marked gender dimorphism in adult rats.

Semin Perinatol 2010 Jun;34(3):193-200

INSERM U954, Nancy-Université, Faculté de Médecine, Nancy, France.

Although recent studies have documented compensatory generation of neurons in adult brains in response to various insults, a noninjurious short episode of hypoxia in rat neonates has been shown to trigger neurogenesis within the ensuing weeks, without apparent brain lesions. Very little is known of the long-term consequences. We therefore investigated the effects of such a conditioning-like hypoxia (100% N(2), 5 min) on the brain and the cognitive outcomes of rats at 40 to 100 days of age. Control and posthypoxic rats developed similar learning capacities over postnatal days 14 to 18, but hypoxia was associated with enhanced scores in a test used to evaluate memory retrieval between 40 and 100 days. A striking sexual dimorphism was observed, with an earlier functional gain observed in female (40 days) compared with male (100 days) rats; gains were associated with matching structural changes in areas involved in cognition, including the hippocampus and frontal cortex. Therefore, it is proposed that brief neonatal hypoxia may exert long-term beneficial effects through neurogenesis stimulation.
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http://dx.doi.org/10.1053/j.semperi.2010.02.003DOI Listing
June 2010

Methyl donor deficiency affects fetal programming of gastric ghrelin cell organization and function in the rat.

Am J Pathol 2010 Jan 30;176(1):270-7. Epub 2009 Nov 30.

INSERM U954, Nutrition, Génétique et Expositions aux Risques Environnementaux, 54505 Vandoeuvre Cedex, France.

Methyl donor deficiency (MDD) during pregnancy influences intrauterine development. Ghrelin is expressed in the stomach of fetuses and influences fetal growth, but MDD influence on gastric ghrelin is unknown. We examined the gastric ghrelin system in MDD-induced intrauterine growth retardation. By using specific markers and approaches (such as periodic acid-Schiff, bromodeoxyuridine, homocysteine, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, immunostaining, reverse transcription-polymerase chain reaction), we studied the gastric oxyntic mucosa cellular organization and ghrelin gene expression in the mucosa in 20-day-old fetuses and weanling pups, and plasma ghrelin concentration in weanling rat pups of dams either normally fed or deprived of choline, folate, vitamin B6, and vitamin B12 during gestation and suckling periods. MDD fetuses weighed less than controls; the weight deficit reached 57% at weaning (P < 0.001). Both at the end of gestation and at weaning, they presented with an aberrant gastric oxyntic mucosa formation with loss of cell polarity, anarchic cell migration, abnormal progenitor differentiation, apoptosis, and signs of surface layer erosion. Ghrelin cells were abnormally located in the pit region of oxyntic glands. At weaning, plasma ghrelin levels were decreased (-28%; P < 0.001) despite unchanged mRNA expression in the stomach. This decrease was associated with lower body weight. Taken together, these data indicate that one mechanism through which MDD influences fetal programming is the remodeling of gastric cellular organization, leading to dysfunction of the ghrelin system and dramatic effects on growth.
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http://dx.doi.org/10.2353/ajpath.2010.090153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797889PMC
January 2010

Differentiation and neural integration of hippocampal neuronal progenitors: signaling pathways sequentially involved.

Hippocampus 2010 Aug;20(8):949-61

Inserm U954, Vandoeuvre-lès-Nancy, F-54500, France.

In the context of their potential implication in regenerative strategies, we characterized cell mechanisms underlying the fate of embryonic rat hippocampal H19-7 progenitors in culture upon induction of their differentiation, and tested their capacities to integrate into a neuronal network in vitro. Without addition of growth factors, nearly 100% of cells expressed various neuronal markers, with a progressive rise of the expression of Synapsin I and II, suggesting that cells developed as mature neurons with synaptogenic capacities. Fully differentiated neurons were identified as glutamatergic and expressed the receptor-associated protein PSD-95. Quantification of ATP showed that 60% of cells died within 24 h after differentiation. Cell death was shown to imply Erk1/2-dependent intrinsic mitochondrial apoptosis signaling pathway, with activation of caspase-9 and -3, finally leading to single-strand DNA. Surviving neurons displayed high levels of Akt, phospho-Akt, and antiapoptotic proteins such as Bcl-2 and Bcl-XL, with decreased caspase activation. In the absence of trophic support, the proapoptotic death-associated protein (DAP) kinase was dramatically stimulated by 24 h postdifferentiation, along with increased levels of p38 and phospho-p38, and caspase reactivation. These findings show that different signaling pathways are sequentially triggered by differentiation, and highlight that ultimate cell death would involve p38 and DAP kinase activation. This was supported by the improvement of cell survival at 24-h postdifferentiation when cells were treated by PD169316, a specific inhibitor of p38. Finally, when seeded on rat hippocampal primary cultured neurons, a significant number of differentiated H19-7 cells were able to survive and to develop cell-cell communication.
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http://dx.doi.org/10.1002/hipo.20690DOI Listing
August 2010

Short hypoxia could attenuate the adverse effects of hyperhomocysteinemia on the developing rat brain by inducing neurogenesis.

Exp Neurol 2009 Mar 10;216(1):231-8. Epub 2008 Dec 10.

INSERM U724, Faculté de Médecine, Vandoeuvre-lès-Nancy, France.

Gestational deficiency in methyl donors such as folate and vitamin B12 impairs homocysteine metabolism and can alter brain development in the progeny. Since short hypoxia has been shown to be neuroprotective in preconditioning studies, we aimed to investigate the effects of brief, non-lesioning neonatal hypoxia (100% N2 for 5 min) on the developing brain of rats born to dams fed either a standard diet or a diet lacking vitamins B12, B2, folate and choline until offspring's weaning. While having no influence on brain accumulation of homocysteine and concomitant apoptosis in 21-day-old deficient pups, exposure to hypoxia reduced morphological injury of the hippocampal CA1 layer. It also markedly stimulated the incorporation of bromodeoxyuridine (BrdU) in permissive areas such as the subventricular zone and the hippocampus followed by the migration of new neurons. Scores in a locomotor coordination test (days 19-21) and learning and memory behavior in the eight-arm maze (days 80-84) were found to be significantly improved in rats exposed to hypoxia in addition to the deficient diet. Therefore, by stimulating neurogenesis in rat pups, brief neonatal hypoxia appeared to attenuate the long-term effects of early exposure to a deficiency in nutritional determinants of hyperhomocysteinemia.
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http://dx.doi.org/10.1016/j.expneurol.2008.11.020DOI Listing
March 2009

Gestational vitamin B deficiency leads to homocysteine-associated brain apoptosis and alters neurobehavioral development in rats.

Am J Pathol 2007 Feb;170(2):667-79

INSERM U.724, Faculté de Médecine, 9 Avenue de la Forêt de Haye, B.P. 184, 54500 Vandoeuvre-lès-Nancy, France.

Hyperhomocysteinemia has been identified as a risk factor for neurological disorders. To study the influence of early deficiency in nutritional determinants of hyperhomocysteinemia on the developing rat brain, dams were fed a standard diet or a diet lacking methyl groups during gestation and lactation. Homocysteinemia progressively increased in the offspring of the deficient group and at 21 days reached 13.3+/-3.7 micromol/L versus 6.8+/-0.3 micromol/L in controls. Homocysteine accumulated in both neurons and astrocytes of selective brain structures including the hippocampus, the cerebellum, the striatum, and the neurogenic subventricular zone. Most homocysteine-positive cells expressed p53 and displayed fragmented DNA indicative of apoptosis. Righting reflex and negative geotaxis revealed a delay in the onset of integration capacities in the deficient group. Between 19 and 21 days, a poorer success score was recorded in deficient animals in a locomotor coordination test. A switch to normal food after weaning allowed restoration of normal homocysteinemia. Nevertheless, at 80 days of age, the exploratory behavior in the elevated-plus maze and the learning and memory behavior in the eight-arm maze revealed that early vitamin B deprivation is associated with persistent functional disabilities, possibly resulting from the ensuing neurotoxic effects of homocysteine.
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http://dx.doi.org/10.2353/ajpath.2007.060339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1851855PMC
February 2007

Mouse bone marrow contains large numbers of functionally competent neutrophils.

J Leukoc Biol 2004 Apr 23;75(4):604-11. Epub 2003 Dec 23.

Laboratoire de Biologie Expérimentale-Immunologie, Faculté des Sciences, Université de Nancy 1, Vandoeuvre, France.

The mouse has become an important model for immunological studies including innate immunity. Creating transgenic mice offers unique possibilities to study gene-function relationships. However, relatively little is known about the physiology of neutrophils from wild-type mice. Do they behave like human neutrophils, or are there species-specific differences that need to be considered when extrapolating results from mice to humans? How do we isolate neutrophils from mice? For practical reasons, many studies on mouse neutrophils are done with bone marrow cells. However, human bone marrow neutrophils appear to be heterogeneous and functionally immature. We have isolated and compared neutrophils from mouse bone marrow and from peripheral blood obtained by tail bleeding. Using the same Percoll density gradient for both preparations, we have obtained morphologically mature neutrophils from bone marrow and blood. Both cell populations responded to formylmethionyl-leucyl-phenylalanine (fMLF) with primary and secondary granule release and superoxide production. Quantitative analysis of our data revealed minor differences between cells from bone marrow and blood. Superoxide production and primary granule release were stimulated at lower fMLF concentrations in blood neutrophils. However, the amplitude and the kinetics of maximal responses were similar. The principal difference was the lifespan of the two cell populations. Bone marrow cells survived significantly longer in culture, which may suggest that they are receiving antiapoptic signals that are absent in the blood. Our data suggest that mice have a large reservoir of functionally competent neutrophils in their bone marrow. This reservoir may be needed to replace circulating neutrophils rapidly during infection.
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http://dx.doi.org/10.1189/jlb.0703340DOI Listing
April 2004

The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis.

J Cell Biol 2002 May 28;157(5):761-70. Epub 2002 May 28.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, 67404 Illkirch Cedex, C.U. de Strasbourg, France.

Trefoil factor (TFF)1 is synthesized and secreted by the normal stomach mucosa and by the gastrointestinal cells of injured tissues. The link between mouse TFF1 inactivation and the fully penetrant antropyloric tumor phenotype prompted the classification of TFF1 as a gastric tumor suppressor gene. Accordingly, altered expression, deletion, and/or mutations of the TFF1 gene are frequently observed in human gastric carcinomas. The present study was undertaken to address the nature of the cellular and molecular mechanisms targeted by TFF1 signalling. TFF1 effects were investigated in IEC18, HCT116, and AGS gastrointestinal cells treated with recombinant human TFF1, and in stably transfected HCT116 cells synthesizing constitutive or doxycycline-induced human TFF1. We observed that TFF1 triggers two types of cellular responses. On one hand, TFF1 lowers cell proliferation by delaying G1-S cell phase transition. This results from a TFF1-mediated increase in the levels of cyclin-dependent kinase inhibitors of both the INK4 and CIP subfamilies, leading to lower E2F transcriptional activity. On the other hand, TFF1 protects cells from chemical-, anchorage-free-, or Bad-induced apoptosis. In this process, TFF1 signalling targets the active form of caspase-9. Together, these results provide the first evidence of a dual antiproliferative and antiapoptotic role for TFF1. Similar paradoxical functions have been reported for tumor suppressor genes involved in cell differentiation, a function consistent with TFF1.
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http://dx.doi.org/10.1083/jcb200108056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173421PMC
May 2002