Publications of Thierry GRISAR
Bookmark and Share    
Full Text
See detailSubtle brain developmental abnormalities in the pathogenesis of juvenile myoclonic epilepsy
Gilsoul, Maxime ULiege; Grisar, Thierry ULiege; Delgado-Escueta, Antonio V et al

in Frontiers in Cellular Neuroscience (2019), 13

Detailed reference viewed: 39 (2 ULiège)
Full Text
See detailVariant intestinal-cell kinase in juvenile myoclonic epilepsy
bailey, JN; de Nijs, L; Bai, D et al

in New England Journal of Medicine (2018), 378

Detailed reference viewed: 52 (9 ULiège)
Full Text
See detailImportin-8 Modulates Division of Apical Progenitors, Dendritogenesis and Tangential Migration During Development of Mouse Cortex.
Nganou, Gerry; Gomes Da Silva, Carla ULiege; Gladwyn-Ng, Ivan ULiege et al

in Frontiers in Molecular Neuroscience (2018), 11

The building of the brain is a multistep process that requires the coordinate expression of thousands of genes and an intense nucleocytoplasmic transport of RNA and proteins. This transport is mediated by ... [more ▼]

The building of the brain is a multistep process that requires the coordinate expression of thousands of genes and an intense nucleocytoplasmic transport of RNA and proteins. This transport is mediated by karyopherins that comprise importins and exportins. Here, we investigated the role of the ss-importin, importin-8 (IPO8) during mouse cerebral corticogenesis as several of its cargoes have been shown to be essential during this process. First, we showed that Ipo8 mRNA is expressed in mouse brain at various embryonic ages with a clear signal in the sub-ventricular/ventricular zone (SVZ/VZ), the cerebral cortical plate (CP) and the ganglionic eminences. We found that acute knockdown of IPO8 in cortical progenitors reduced both their proliferation and cell cycle exit leading to the increase in apical progenitor pool without influencing the number of basal progenitors (BPs). Projection neurons ultimately reached their appropriate cerebral cortical layer, but their dendritogenesis was specifically affected, resulting in neurons with reduced dendrite complexity. IPO8 knockdown also slowed the migration of cortical interneurons. Together, our data demonstrate that IPO8 contribute to the coordination of several critical steps of cerebral cortex development. These results suggest that the impairment of IPO8 function might be associated with some diseases of neuronal migration defects. [less ▲]

Detailed reference viewed: 41 (3 ULiège)
Full Text
See detailImportin-8 could cause CAE/JME by delaying early neuroblast migration
Nganou, Gerry ULiege; Tanaka, Miyabi; Coumans, Bernard ULiege et al

Poster (2017, April 27)

Abstract : Childhood Absence Evolving to Juvenile Myoclonic Epilepsy (CAE/JME) is an uncommon form of genetic generalized epilepsy that appears as absence in childhood and evolves into generalized ... [more ▼]

Abstract : Childhood Absence Evolving to Juvenile Myoclonic Epilepsy (CAE/JME) is an uncommon form of genetic generalized epilepsy that appears as absence in childhood and evolves into generalized tonic–clonic seizures with myoclonic jerks during adolescence. In some family of patients affected by CAE/JME, mutations have been observed in the gene encoding for the transport protein importin-8 (IPO8). IPO8 could be at the origin of CAE/JME via its role in the transport of its targets (like Ago-2, Smad4, c-Jun). RT-qPCR has shown that IPO8 mRNA is expressed at all ages with no big difference in expression level. Using ISH, a clear expression of mIPO8 mRNA was observed in the sub-ventricular/ventricular zone (SVZ/VZ), the cortical plate (CP) and the ganglionic eminences (GE) of developing brain at E14. Both SVZ/VZ and GE are the “neurogenic niches” that generate glutamatergic and GABAergic neurons respectively. The implication of IPO8 in the generation of “glutamatergic neurons” was investigated by In Utero electroporation (IUE) and MGE Electroporation. Using shRNA, we observed that after 3 days, “glutamatergic neuroblasts” do not reach the CP in contrast to the control condition. This effect can be rescued by the co-expression of a form of IPO8 that is resistant to the shRNA. When overexpressing the pathological forms of hIPO8, but not a variant, migration of “glutamatergic neuroblasts” was also impaired. However, when the observation is made later, i.e. at P5, we observed that the neuroblasts finally reach their correct layer in the cortex, suggesting IPO8 only delayed but not blocked migration. Moreover, shRNA against IPO8 mRNA lead to alteration of interneurons (GABAergic neurons) migration same to overexpression of one mutated form of IPO8. Conclusion : IPO8 is expressed in mouse brain during development. It shows a clear expression during embryogenesis in the “neurogenic niches”. Moreover, IPO8 modulates neuroblasts (radial and tangential) migration in the developing brain. So, abnormal brain development due to IPO8 mutations could be at the origin of CAE/JME. [less ▲]

Detailed reference viewed: 80 (18 ULiège)
Full Text
See detailEFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality
Bailey, JN; Patterson, C; de Nijs, L et al

in Genetics in Medicine (2017), 19

Detailed reference viewed: 215 (5 ULiège)
Full Text
See detailImportin-8 mutations could cause Jeavons Syndrome, CAE and JME by altering early neuroblast migration
Nganou, Gerry ULiege; Tanaka, Miyabi; Coumans, Bernard ULiege et al

Poster (2016, December)

Jeavons syndrome (JS) is an uncommon form of juvenile epilepsy. In some family affected by JS, the gene of importin-8 (IPO8) a member of karyopherin superfamily of proteins, has been found mutated ... [more ▼]

Jeavons syndrome (JS) is an uncommon form of juvenile epilepsy. In some family affected by JS, the gene of importin-8 (IPO8) a member of karyopherin superfamily of proteins, has been found mutated. Karyopherin are known to regulate nucleo-cytoplasmic transport of many proteins. IPO8, a member of the β-karyopherin sub-family, is reported to control the transport Ago-2, c-Jun and Smad-4 for example, three proteins important for brain development. Here, we show that IPO8 is well expressed in mouse brain at embryonic stage. Moreover inhibition of IPO8 mRNA by shRNA in-utéro-electroporation (IUE), impairs early neuroblast migration as weel as IUE overexpression of mutated form of human IPO8. So, abnormal brain development due to IPO8 mutations could be at the origin of Jeavons Syndrome, Chilhood abscence evolving (CAE) and/or juvenile myoclonic epilepsy (JME). [less ▲]

Detailed reference viewed: 148 (12 ULiège)
See detailEFHC1/Myoclonin-1 modulates the post-translational modification of microtubules
Medard, Laurie ULiege; Godin, Juliette; Coumans, Bernard ULiege et al

Poster (2015, December)

Rationale: Juvenile myoclonic epilepsies (JME) are one of the most common forms of genetic generalized epilepsy. Genetic studies have shown that heterozygous mutations in EFHC1/Myoclonin1 are responsible ... [more ▼]

Rationale: Juvenile myoclonic epilepsies (JME) are one of the most common forms of genetic generalized epilepsy. Genetic studies have shown that heterozygous mutations in EFHC1/Myoclonin1 are responsible for 3-22% of JME cases worldwide. The Myoclonin1 protein contains three DM10 domains of unknown function and an EF-hand domain. We have previously demonstrated that Myoclonin1 is a microtubule-associated protein involved in cell division and radial migration during neocortex development. In cells, this protein co-localized with specific structures rich in microtubules (MTs) such as the centrosome, the poles of the mitotic spindle or the motile cilia but not with cytoplasmic MTs. This suggests post-translational modifications (PTM) of MTs may be important for the interaction between Myoclonin1 and MTs Methods: We co-expressed the different enzymes catalyzing PTM of MTs with Myoclonin1 in U2OS cell line, and then performed immunocytochemistry and western blot analysis. We next performed pulldown and luciferase complementation assays to test protein interaction Results: With one of these enzymes, we observed a strong increase in PTM in the presence of Myoclonin- 1.Interestingly, the effect is observed even when a DM10 domain alone is co-expressed with the enzyme, suggesting for the first time a role for this domain. This suggests that Myoclonin1 may interact with and modulate the activity of this enzyme. By using luciferase complementation assay and pull down experiments, we could demonstrate that both proteins interact. Conclusions: Our data suggest Myoclonin-1 modulates specific PTM of MTs. This is of prime importance for microtubule dynamic and notably for neuroblast precursor migration during neocortex development. This could be the mechanism that explains why pathological forms of myoclonin-1 may affect brain development. [less ▲]

Detailed reference viewed: 60 (26 ULiège)
Full Text
See detailUnusual Amino Acids and Monofluoroacetate from Dichapetalum michelsonii (Umutambasha), a Toxic Plant from Rwanda
Esters, Virginie ULiege; Karangwa, Charles; Tits, Monique ULiege et al

in Planta Medica (2013), 79

In the course of our investigations on Umutambasha in order to identify its convulsant principles, small quantities of monofluoroacetate were observed in stem bark, leaves, and fruits of this plant newly ... [more ▼]

In the course of our investigations on Umutambasha in order to identify its convulsant principles, small quantities of monofluoroacetate were observed in stem bark, leaves, and fruits of this plant newly identified as Dichapetalum michelsonii Hauman. Conclusive evidence for a monofluoroacetate presence came from its isolation from the freeze-dried extract of stem bark. Three free unusual amino acids, named N-methyl-α-alanine, N-methyl-β-alanine, and 2,7-diaminooctan-1,8-dioic acid, described for the first time in a plant, and known trigonelline were also isolated from the stem bark of D. michelsonii. Structure elucidations were mainly achieved by spectroscopic methods (1H-NMR, 2D-NMR, MS) and by comparison with authentic references. These unusual amino acids were detected by a fast, reliable TLC analysis in all our batches of Umutambasha, suggesting that they could be used for identification purposes in case of human or livestock intoxications. Finally, EEG recordings and behavioural observations performed in mice suggested that the convulsive patterns produced by Umutambasha are the consequence of monofluoroacetate presence in D. michelsonii. [less ▲]

Detailed reference viewed: 63 (9 ULiège)
Full Text
See detailMyoclonin1/EFHC1 in cell division, neuroblast migration, synapse/dendrite formation in juvenile myoclonic epilepsy
Grisar, Thierry ULiege; Lakaye, Bernard ULiege; de Nijs, Laurence ULiege et al

in Noebels, JL; Avoli, M; Rogawski, MA (Eds.) et al Jasper's Basic Mechanisms of the Epilepsies, 4th edition (2012)

Detailed reference viewed: 63 (4 ULiège)
Full Text
See detailThiamine Status in Humans and Content of Phosphorylated Thiamine Derivatives in Biopsies and Cultured Cells
Gangolf, Marjorie ULiege; Czerniecki, Jan; Radermecker, Marc ULiege et al

in PLoS ONE (2010), 5(10), 13616

Background Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine ... [more ▼]

Background Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines. Methodology and Principal Findings Thiamine derivatives were determined by HPLC. In human tissues, the total thiamine content is lower than in other animal species. ThDP is the major thiamine compound and tissue levels decrease at high age. In semen, ThDP content correlates with the concentration of spermatozoa but not with their motility. The proportion of ThTP is higher in humans than in rodents, probably because of a lower 25-kDa ThTPase activity. The expression and activity of this enzyme seems to correlate with the degree of cell differentiation. ThTP was present in nearly all brain and muscle samples and in ~60% of other tissue samples, in particular fetal tissue and cultured cells. A low ([ThTP]+[ThMP])/([Thiamine]+[ThMP]) ratio was found in cardiovascular tissues of patients with cardiac insufficiency. AThTP was detected only sporadically in adult tissues but was found more consistently in fetal tissues and cell lines. Conclusions and Significance The high sensitivity of humans to thiamine deficiency is probably linked to low circulating thiamine concentrations and low ThDP tissue contents. ThTP levels are relatively high in many human tissues, as a result of low expression of the 25-kDa ThTPase. Another novel finding is the presence of ThTP and AThTP in poorly differentiated fast-growing cells, suggesting a hitherto unsuspected link between these compounds and cell division or differentiation. [less ▲]

Detailed reference viewed: 97 (31 ULiège)
Full Text
See detailL’OBSERVANCE THERAPEUTIQUE DU PATIENT SOUFFRANT D’EPILEPSIE. Un problème fréquent et complexe.
RIKIR, Estelle ULiege; Grisar, Thierry ULiege; SADZOT, Bernard ULiege

in Revue Médicale de Liège (2010), 65(5-6), 370-380

Epilepsy is a chronic disease, requiring a medical treatment which is essentially preventive (avoiding further seizure). Because of these characteristics, one third to one half of the epileptic patients ... [more ▼]

Epilepsy is a chronic disease, requiring a medical treatment which is essentially preventive (avoiding further seizure). Because of these characteristics, one third to one half of the epileptic patients does not always comply with their treatment. In this article, we review the different factors of poor compliance. Some are specific to this medical condition while others are more general, like treatment complexity. We list here some suggestions to improve the compliance of the epileptic patient in routine medical practice. [less ▲]

Detailed reference viewed: 112 (5 ULiège)
Full Text
See detailDistribution of EFHC1 or myoclonin 1 in mouse neural structures
Leon, Christine ULiege; de Nijs, Laurence ULiege; Chanas, Grazyna et al

in Epilepsy Research (2010), 88

Detailed reference viewed: 55 (6 ULiège)
Full Text
See detailMajor impairments of glutamatergic transmission and long term synaptic plasticity in the hippocampus of mice lacking the melanin-concentrating hormone receptor-1
Pachoud, Bastien; Adamantidis, Antoine ULiege; Ravassard, Pascal et al

in Journal of Neurophysiology (2010), 104

Detailed reference viewed: 58 (9 ULiège)
Full Text
See detailMelanin-concentrating hormone and immune function
Lakaye, Bernard ULiege; Coumans, Bernard ULiege; Harray, Sophie ULiege et al

in Peptides (2009), 30

To date,melanin-concentrating hormone (MCH) has been generally considered as peptide acting almost exclusively in the central nervous system. In the present paper, we revise the experimental evidence ... [more ▼]

To date,melanin-concentrating hormone (MCH) has been generally considered as peptide acting almost exclusively in the central nervous system. In the present paper, we revise the experimental evidence, demonstrating that MCH and its receptors are expressed by cells of the immune system and directly influence the response of these cells in some circumstances. This therefore supports the idea that, as with other peptides, MCH could be considered as a modulator of the immune system. Moreover, we suggest that this could have important implications in several immune-mediated disorders and affirm that there is a clear need for further investigation [less ▲]

Detailed reference viewed: 43 (8 ULiège)
See detailCytoskeletal genes and idiopathic epilepsies
Lakaye, Bernard ULiege; de Nijs, Laurence ULiege; Leon, Christine et al

in Schwartzkroin, A. (Ed.) Encyclopedia of Basic Epilepsy Research (2009)

Detailed reference viewed: 15 (3 ULiège)
Full Text
See detailEFHC1 interacts with microtubules to regulate cell division and cortical development
de Nijs, Laurence ULiege; Leon, Christine ULiege; Nguyen, Laurent ULiege et al

in Nature Neuroscience (2009), 12(10), 1266-74

Mutations in the EFHC1 gene are linked to juvenile myoclonic epilepsy (JME), one of the most frequent forms of idiopathic generalized epilepsies. JME is associated with subtle alterations of cortical and ... [more ▼]

Mutations in the EFHC1 gene are linked to juvenile myoclonic epilepsy (JME), one of the most frequent forms of idiopathic generalized epilepsies. JME is associated with subtle alterations of cortical and subcortical architecture, but the underlying pathological mechanism remains unknown. We found that EFHC1 is a microtubule-associated protein involved in the regulation of cell division. In vitro, EFHC1 loss of function disrupted mitotic spindle organization, impaired M phase progression, induced microtubule bundling and increased apoptosis. EFHC1 impairment in the rat developing neocortex by ex vivo and in utero electroporation caused a marked disruption of radial migration. We found that this effect was a result of cortical progenitors failing to exit the cell cycle and defects in the radial glia scaffold organization and in the locomotion of postmitotic neurons. Therefore, we propose that EFHC1 is a regulator of cell division and neuronal migration during cortical development and that disruption of its functions leads to JME [less ▲]

Detailed reference viewed: 109 (32 ULiège)
Full Text
See detailEffects of the H(3) receptor inverse agonist thioperamide on cocaine-induced locomotion in mice: role of the histaminergic system and potential pharmacokinetic interactions.
Brabant, Christian ULiege; Alleva, Livia ULiege; Grisar, Thierry ULiege et al

in Psychopharmacology (2009), 202(4), 673-87

RATIONALE: Previous studies have shown that intraperitoneal injections of thioperamide, an imidazole-based H(3) receptor inverse agonist that enhances histamine release in the brain, potentiate cocaine ... [more ▼]

RATIONALE: Previous studies have shown that intraperitoneal injections of thioperamide, an imidazole-based H(3) receptor inverse agonist that enhances histamine release in the brain, potentiate cocaine-induced hyperlocomotion. The present study examined the involvement of the histaminergic system in these effects of thioperamide in mice. MATERIALS AND METHODS: We investigated whether immepip, a selective H(3) agonist, could reverse the potentiating effects of thioperamide. Moreover, the non-imidazole H(3) inverse agonist A-331440 was tested on the locomotor effects of cocaine. Using high-performance liquid chromatography with ultraviolet detection, cocaine plasma concentrations were measured to study potential drug-drug interactions between thioperamide and cocaine. Finally, thioperamide was tested on the locomotor effects of cocaine in histamine-deficient knockout mice in order to determine the contribution of histamine to the modulating effects of thioperamide. RESULTS: Thioperamide potentiated cocaine-induced hyperlocomotion in normal mice, and to a higher extent, in histamine-deficient knockout mice. A-331440 only slightly affected the locomotor effects of cocaine. Immepip did not alter cocaine-induced hyperactivity but significantly reduced the potentiating actions of thioperamide on cocaine's effects. Finally, plasma cocaine concentrations were more elevated in mice treated with thioperamide than in mice that received cocaine alone. CONCLUSIONS: The present results indicate that histamine released by thioperamide through the blockade of H(3) autoreceptors is not involved in the ability of this compound to potentiate cocaine induced-hyperactivity. Our data suggest that thioperamide, at least at 10 mg/kg, increases cocaine-induced locomotion through the combination of pharmacokinetic effects and the blockade of H(3) receptors located on non-histaminergic neurons. [less ▲]

Detailed reference viewed: 103 (16 ULiège)