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8 results on '"Fondation NRJ-Institut de France"'

1. APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation

Author

Arnaud, Laurie, Benech, Philippe, Greetham, Louise, Stephan, Delphine, Jimenez, Angélique, Jullien, Nicolas, García-González, Laura, Tsvetkov, Philipp, Devred, François, Sancho-Martinez, Ignacio, Izpisua Belmonte, Juan Carlos, Baranger, Kévin, Rivera, Santiago, Nivet, Emmanuel, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), FAES farma, Altos Labs, Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS), ANR-21-CE17-0047,TRANS3,TAGLN3, un nouveau régulateur de la neuroinflammation: un biomarqueur et une cible thérapeutique dans la maladie d'Alzheimer(2021), LIttoral ENvironnement et Sociétés (LIENSs), La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), and This work was supported by the CNRS and Aix Marseille Universite´.The work was also supported by the DHUNE Center of Excellence and a CoEN grant (to S.R. and E.N.), by the ‘‘FONDATION ALZHEIMER’’ (to S.R. and E.N.), by ‘‘Fondation Vaincre Alzheimer’’ (FR-19052 to E.N.), by ‘‘La Fondation NRJ-Institut de France’’ to E.N., by l’Agence Nationale de la Recherche (ANR) (ANR-21-CE17-0047-01 to E.N.), and by a CoEN grant to S.R. and E.N. L.G.-G. was supported by an ANR grant (MAD5) to S.R. and also by grants from the Fondation pour la Recherche Me´dicale FRM FDT201904008423 and by a Fondation Vaincre Alzheimer international travel grant. This work has received support from the French government under the Programme Investissements d’Avenir, Initiative d’Excellence d’Aix-Marseille Universite´ via A*Midex (AMX-19-IET-004) and ANR (ANR17-EURE-0029) funding.

Subjects
[SDV]Life Sciences [q-bio]
Abstract

International audience; Apolipoprotein E4 (APOEε4) is the major allelic risk factor for late-onset sporadic Alzheimer’s disease (sAD). Inflammation is increasingly considered as critical in sAD initiation and progression. Identifying brain molecular mechanisms that could bridge these two risk factors remain unelucidated. Leveraging induced pluripotent stem cell (iPSC)-based strategies, we demonstrate that APOE controls inflammation in human astrocytes by regulating Transgelin 3 (TAGLN3) expression and, ultimately, nuclear factor kB (NF-kB) activation. We uncover that APOE4 specifically downregulates TAGLN3, involving histone deacetylases activity, which results in low-gradechronicinflammationandhyperactivatedinflammatoryresponses.Weshow that APOE4 exerts a dominant negative effect to prime astrocytes toward a pro-inflammatory state that is pharmacologically reversible by TAGLN3 supplementation. We further confirm that TAGLN3 is downregulated in the brainofpatientswithsAD.OurfindingshighlighttheAPOE-TAGLN3-NF-kBaxisregulatingneuroinflammation in human astrocytes and reveal TAGLN3 as amolecular target to modulate neuroinflammation, as well as a potential biomarker for AD.

Published
2022

2. The role of sleep in emotional processing: insights and unknowns from rodent research

Author

Gabrielle Girardeau, Marco N Pompili, Stéphanie Trouche, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ATIP-Avenir grant, The Fyssen Foundation, Emergence(s) Ville de Paris, NARSAD Young Investigator Grants from the Brain and Behavior Research Foundation, Fondation NRJ-Institut de France, Fondation Pierre Deniker, and ANR-19-CE37-0006,DYNAFEAR,Dynamique des ensembles neuronaux au sein du circuit amygdalo-striatal pendant l'extinction et le retour de la peur(2019)

Subjects
0301 basic medicine, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Physiology, Hippocampus, Cognition, Engram, Amygdala, Sleep in non-human animals, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Physiology (medical), [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Memory consolidation, Fear conditioning, Psychology, Prefrontal cortex, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Sleep is essential for the regulation of neural dynamics and animal behavior. In particular, sleep is crucial for memory consolidation and emotional regulation. In turn, emotions are key to the modulation of learning processes in which sleep also plays a crucial role. Emotional processing triggers coordinated activity between neuronal populations embedded in a network including the hippocampus, amygdala and prefrontal cortex. The optogenetic modulation of these distributed engrams' activity interferes with emotional memory. During non-REM sleep, cross-structure coordinated replay may underpin the consolidation of brain-wide emotional associative engrams. Fear conditioning induces neural synchronization between the amygdala, hippocampus, and medial prefrontal cortex during subsequent REM sleep, the perturbation of which interferes with fear memory consolidation. Future work may focus on the differential mechanisms during REM vs non-REM sleep that underpin emotional regulation and memory consolidation, as well as on distinguishing between these two tightly linked cognitive processes.

Published
2020

3. Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy

Author

Ryan J. Weiss, Sébastien Blondeel, Mohamed Bennis, Constantin Yanicostas, Nadia Soussi-Yanicostas, Seyedeh Maryam Alavi Naini, Rahma Hassan-Abdi, Yitzhak Tor, Jeffrey D. Esko, Université de Paris, NeuroDiderot, Inserm U1141, F-75019 Paris, France, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Cadi Ayyad [Marrakech] (UCA), Department of Chemistry and Biochemistry, University of California [San Diego] (UC San Diego), University of California-University of California, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry and Biochemistry [La Jolla, CA, USA], Department of Cellular and Molecular Medicine (CMM), SMAN received a grant from Servier Research Institute. This work was supported by Institut National de la Santé et la Recherche Médicale (INSERM), the French National Research Agency (ANR-16-CE18–0010), and Fondation NRJ (Institut de France) to NSY and grants CA46462 and CA112278 from the National Institute of Health to JDE and YT., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California (UC)-University of California (UC), yanicostas, constantin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), BMC, BMC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Aging, [SDV]Life Sciences [q-bio], Heparan sulfate, Neurodegenerative, lcsh:RC346-429, chemistry.chemical_compound, 0302 clinical medicine, Oxalyl surfen, 2.1 Biological and endogenous factors, Aetiology, Zebrafish, biology, medicine.diagnostic_test, Chemistry, Alzheimer's disease, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], MESH: Tauopathy, Zebrafish, Alzheimer’s disease, Tau protein, Tau hyperphosphorylation, Surfen, Oxalyl surfen, Heparan sulfate, Tauopathy, medicine.anatomical_structure, 5.1 Pharmaceuticals, Neurological, Surfen, Tau hyperphosphorylation, Development of treatments and therapeutic interventions, Alzheimer’s disease, Cognitive Neuroscience, Tau protein, Clinical Sciences, Short Report, 03 medical and health sciences, Cellular and Molecular Neuroscience, Western blot, In vivo, medicine, Acquired Cognitive Impairment, lcsh:Neurology. Diseases of the nervous system, Antagonist, Neurosciences, Correction, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), biology.organism_classification, medicine.disease, Brain Disorders, 030104 developmental biology, biology.protein, Dementia, Neurology (clinical), Neuron, 030217 neurology & neurosurgery
Abstract

Background Tauopathies comprise a family of neurodegenerative disorders including Alzheimer’s disease for which there is an urgent and unmet need for disease-modifying treatments. Tauopathies are characterized by pathological tau hyperphosphorylation, which has been shown to correlate tightly with disease progression and memory loss in patients suffering from Alzheimer’s disease. We recently demonstrated an essential requirement for 3-O-sulfated heparan sulfate in pathological tau hyperphosphorylation in zebrafish, a prominent model organism for human drug discovery. Here, we investigated whether in vivo treatment with surfen or its derivatives oxalyl surfen and hemisurfen, small molecules with heparan sulfate antagonist properties, could mitigate tau hyperphosphorylation and neuronal deficits in a zebrafish model of tauopathies. Results In vivo treatment of Tg[HuC::hTauP301L; DsRed] embryos for 2 days with surfen or oxalyl surfen significantly reduced the accumulation of the pThr181 tau phospho-epitope measured by ELISA by 30% and 51%, respectively. Western blot analysis also showed a significant decrease of pThr181 and pSer396/pSer404 in embryos treated with surfen or oxalyl surfen. Immunohistochemical analysis further confirmed that treatment with surfen or oxalyl surfen significantly decreased the AT8 tau epitope in spinal motoneurons. In addition, in vivo treatment of Tg[HuC::hTauP301L; DsRed] embryos with surfen or oxalyl surfen significantly rescued spinal motoneuron axon-branching defects and, as a likely consequence, the impaired stereotypical touch-evoked escape response. Importantly, treatment with hemisurfen, a surfen derivative devoid of heparan sulfate antagonist activity, does not affect tau hyperphosphorylation, nor neuronal or behavioural deficits in Tg[HuC::hTauP301L; DsRed] embryos. Conclusion Our findings demonstrate for the first time that surfen, a well-tolerated molecule in clinical settings, and its derivative, oxalyl surfen, could mitigate or delay neuronal defects in tauopathies, including Alzheimer’s disease.

Published
2018

4. Effects of L-DOPA and STN-HFS dyskinesiogenic treatments on NR2B regulation in basal ganglia in the rat model of Parkinson's disease.: NR2B hyperphosphorylation driven by L-DOPA and STN-HFS

Author

Quintana, Adrien, Sgambato-Faure, Véronique, Savasta, Marc, INSERM U836, équipe 10, Dynamique des réseaux neuronaux du mouvement, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale, le Ministère de la Recherche et des Nouvelles Technologies, Région Rhône-Alpes (Cluster no.11), Association France Parkinson, and Fondation NRJ-Institut de France.

Subjects
nervous system, musculoskeletal, neural, and ocular physiology, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], nervous system diseases
Abstract

International audience; Dyskinesia is a major side effect of chronic levodopa (L-DOPA) administration, the reference treatment for Parkinson's disease (PD). High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing L-DOPA requirement. However, inadequate stimulation can also trigger dyskinetic movements in PD patients and animal models. Here, we investigated the possible association between L-DOPA- and STN-HFS-induced dyskinesia and regulation of the NR2B subunit of NMDA receptors in the rodent model of PD. We subjected 6-OHDA-lesioned rats to HFS for 1h, at an intensity triggering forelimb dyskinesia. Other 6-OHDA-lesioned rats were treated with chronic high doses of L-DOPA for ten days, to induce abnormal involuntary movements. The 6-OHDA lesion regulated NR2B only in the SNr, where the activation of NR2B was observed (as assessed by phosphorylation of the Tyr(1472) residue). Both STN-HFS and L-DOPA dyskinesiogenic treatments induced NR2B activation in the STN and EP, but only L-DOPA triggered NR2B hyperphosphorylation in the striatum. Finally, the use of CP-101,606 exacerbated L-DOPA-induced motor behavior and associated NR2B hyperphosphorylation in the striatum, STN and EP. Thus, NR2B activation in basal ganglia structures is correlated with dyskinesia.

Published
2012

5. Effects of L-DOPA and STN-HFS dyskinesiogenic treatments on NR2B regulation in basal ganglia in the rat model of Parkinson's disease.: NR2B hyperphosphorylation driven by L-DOPA and STN-HFS

Author

Quintana, Adrien, Sgambato-Faure, Véronique, Savasta, Marc, Savasta, Marc, INSERM U836, équipe 10, Dynamique des réseaux neuronaux du mouvement, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale, le Ministère de la Recherche et des Nouvelles Technologies, Région Rhône-Alpes (Cluster no.11), Association France Parkinson, and Fondation NRJ-Institut de France.

Subjects
nervous system, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], musculoskeletal, neural, and ocular physiology, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], nervous system diseases
Abstract

International audience; Dyskinesia is a major side effect of chronic levodopa (L-DOPA) administration, the reference treatment for Parkinson's disease (PD). High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing L-DOPA requirement. However, inadequate stimulation can also trigger dyskinetic movements in PD patients and animal models. Here, we investigated the possible association between L-DOPA- and STN-HFS-induced dyskinesia and regulation of the NR2B subunit of NMDA receptors in the rodent model of PD. We subjected 6-OHDA-lesioned rats to HFS for 1h, at an intensity triggering forelimb dyskinesia. Other 6-OHDA-lesioned rats were treated with chronic high doses of L-DOPA for ten days, to induce abnormal involuntary movements. The 6-OHDA lesion regulated NR2B only in the SNr, where the activation of NR2B was observed (as assessed by phosphorylation of the Tyr(1472) residue). Both STN-HFS and L-DOPA dyskinesiogenic treatments induced NR2B activation in the STN and EP, but only L-DOPA triggered NR2B hyperphosphorylation in the striatum. Finally, the use of CP-101,606 exacerbated L-DOPA-induced motor behavior and associated NR2B hyperphosphorylation in the striatum, STN and EP. Thus, NR2B activation in basal ganglia structures is correlated with dyskinesia.

Published
2012

6. Forelimb dyskinesia mediated by high-frequency stimulation of the subthalamic nucleus is linked to rapid activation of the NR2B subunit of N-methyl-D-aspartate receptors

Author

Quintana, A., Melon, C., Kerkerian-Le Goff, L., Salin, P., Savasta, M., Sgambato-Faure, V., INSERM U836, équipe 10, Dynamique des réseaux neuronaux du mouvement, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Grenoble Institut des Neurosciences (GIN), INSERM, CNRS, Université de la Méditerrannée, Région Rhône-Alpes, Association France Parkinson, Fondation NRJ-Institut de France, Savasta, Marc, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), and Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Neurons, MESH: Rats, Sprague-Dawley, MESH: Dose-Response Relationship, Drug, Rats, Sprague-Dawley, Piperidines, Thalamus, Forelimb, rat, MESH: Animals, ComputingMilieux_MISCELLANEOUS, Neurons, MESH: Thalamus, subthalamic nucleus, MESH: Statistics, Nonparametric, musculoskeletal, neural, and ocular physiology, Motor Cortex, MESH: Electric Stimulation, Immunohistochemistry, Electrodes, Implanted, MESH: Piperidines, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], high frequency stimulation, MESH: Rats, glutamate, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Receptors, N-Methyl-D-Aspartate, MESH: Motor Cortex, Statistics, Nonparametric, MESH: Analysis of Variance, otorhinolaryngologic diseases, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Subthalamic Nucleus, Analysis of Variance, MESH: Receptors, N-Methyl-D-Aspartate, Dyskinesias, Dose-Response Relationship, Drug, MESH: Dyskinesias, MESH: Dizocilpine Maleate, MESH: Immunohistochemistry, Electric Stimulation, MESH: Male, Rats, nervous system diseases, MESH: Forelimb, body regions, nervous system, CP-101, MESH: Electrodes, Implanted, Dizocilpine Maleate
Abstract

International audience; Dyskinesia is a major side-effect of chronic l-DOPA administration, the reference treatment for Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing the L-DOPA requirement. However, inappropriate stimulation can also trigger dyskinetic movements, in both human and rodents. We investigated whether STN-HFS-evoked forelimb dyskinesia involved changes in glutamatergic neurotransmission as previously reported for L-DOPA-induced dyskinesias, focusing on the role of NR2B-containing N-methyl-D-aspartate receptors (NR2B/NMDARs). We applied STN-HFS in normal rats at intensities above and below the threshold for triggering forelimb dyskinesia. Dyskinesiogenic STN-HFS induced the activation of NR2B (as assessed by immunodetection of the phosphorylated residue Tyr(1472)) in neurons of the subthalamic nucleus, entopeduncular nucleus, motor thalamus and forelimb motor cortex. The severity of STN-HFS-induced forelimb dyskinesia was decreased in a dose-dependent manner by systemic injections of CP-101,606, a selective blocker of NR2B/NMDARs, but was either unaffected or increased by the non-selective N-methyl-D-aspartate receptor antagonist, MK-801.

Published
2010

7. Critical role of the proline-rich region in Huntingtin for aggregation and cytotoxicity in yeast

Author

Anne Bertolotti, Benjamin Dehay, Régulation de l'expression génétique (REG), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Groupement d’Interet Scientifique Infections a` Prions, the Fondation pour La Recherche sur le Cerveau, the Fondation NRJ-Institut de France, INSERM, and the European Molecular Biology Organization Young Investigator Programme., École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), and Dehay, Benjamin

Subjects
Sucrose, Huntingtin, Saccharomyces cerevisiae Proteins, Formates, Proline, [SDV]Life Sciences [q-bio], Green Fluorescent Proteins, Context (language use), Nerve Tissue Proteins, Saccharomyces cerevisiae, Biology, Proline-Rich Region, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Centrifugation, Density Gradient, Humans, HSP70 Heat-Shock Proteins, Cytotoxicity, Molecular Biology, Heat-Shock Proteins, 030304 developmental biology, 0303 health sciences, Huntingtin Protein, Nuclear Proteins, Cell Biology, Molecular biology, Yeast, Hsp70, [SDV] Life Sciences [q-bio], Huntington Disease, Toxic proteins, Microscopy, Fluorescence, Toxicity, Peptides, 030217 neurology & neurosurgery, Gene Deletion, Molecular Chaperones, Protein Binding
Abstract

International audience; Nine neurodegenerative diseases, such as Huntington, are caused by a polyglutamine (poly(Q)) expansion in otherwise unrelated proteins. Although poly(Q) expansion causes aggregation of the affected proteins, the protein context might determine the selective neuronal vulnerability found in each disease. Here we have report that, although expression of Huntingtin derivatives with a pathological poly(Q) expansion are innocuous in yeast, deletion of the flanking proline-rich region alters the shape and number of poly(Q) inclusions and unmasks toxic properties. Strikingly, deletion of Hsp104 increases the size of inclusions formed by expanded poly(Q) lacking the proline-rich region and abolishes toxicity. Overexpression of the chaperones Hsp104 or Hsp70 rescues growth defects in affected cells without resolving inclusions. However, aggregates formed by nontoxic Huntingtin derivatives or by toxic derivatives cured by chaperones are physically distinct from aggregates formed by toxic proteins. This study identifies the proline-rich region in Huntingtin as a profound cis-acting modulator of expanded poly(Q) toxicity and distinguishes between aggregates of toxic or non-toxic proteins.

Published
2006

8. Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures

Author

Carmen I. Badiu, T.I. Tóth, Diego Ruano, Laurence Bourgeais, Vincenzo Crunelli, Nathalie Leresche, Bertrand Lambolez, David Allan Carter, Thomas Bessaïh, Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Physiologie et physiopathologie de la signalisation cellulaire (PPSC), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux]-Centre National de la Recherche Scientifique (CNRS), School of Biosciences [Cardiff], Cardiff University, Depto. de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de farmacia, This work was supported by the Fondation NRJ-Institut de France, the Wellcome Trust (grant 071436) and the Fondo de Investigaciones Sanitarias (grant 03/0177). D.R. is supported by the Ramón y Cajal program from MCYT, Spain. We wish to thank Novartis (Basel, Switzerland) for their gift of CGP 55845A and CGP 35348., and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Baclofen, Physiology, Synaptic Transmission, Membrane Potentials, GABA Antagonists, Propanolamines, Epilepsy, 0302 clinical medicine, Thalamus, gamma-Aminobutyric Acid, 6-Cyano-7-nitroquinoxaline-2,3-dione, 0303 health sciences, GABAA receptor, General Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Immunohistochemistry, medicine.drug, reticular nucleus, seizure, In Vitro Techniques, Biology, GABAB receptor, Neurotransmission, Inhibitory postsynaptic potential, gamma-Aminobutyric acid, 03 medical and health sciences, Organophosphorus Compounds, Genetic model, medicine, Animals, GABA-B receptor, GABA-A Receptor Antagonists, GABA Agonists, 030304 developmental biology, Ventral Thalamic Nuclei, Intralaminar Thalamic Nuclei, ACM, Excitatory Postsynaptic Potentials, Somatosensory Cortex, Receptors, GABA-A, medicine.disease, Phosphinic Acids, Rats, Epilepsy, Absence, GABA-A receptor, Synapses, epilepsy, Neuroscience, 030217 neurology & neurosurgery
Abstract

Human and experimental studies indicate that molecular genetic changes in GABAA receptors may underlie the expression of spike-and-waves discharges (SWDs) occurring during absence seizures. However, the full spectrum of the genetic defects underlying these seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we investigated GABAA inhibitory postsynaptic currents (IPSCs) in key thalamocortical areas, i.e., the somatosensory cortex, ventrobasal thalamus (VB) and nucleus reticularis thalami (NRT), in preseizure genetic absence epilepsy rats from Strasbourg (GAERS), a well-established genetic model of typical absence seizures that shows no additional neurological abnormalities, and compared their properties to age-matched non-epileptic controls (NECs). Miniature GABAA IPSCs of VB and cortical layers II/III neurons were similar in GAERS and NEC, whereas in GAERS NRT neurons they had 25% larger amplitude, 40% faster decay. In addition, baclofen was significantly less effective in decreasing the frequency of NRT mIPSCs in GAERS than in NEC, whereas no difference was observed for cortical and VB mIPSCS between the two strains. Paired-pulse depression was 45% smaller in GAERS NRT, but not in VB, and was insensitive to GABAB antagonists. These results point to subtle, nucleus-specific, GABAA receptor abnormalities underlying SWDs of typical absence seizures rather than a full block of these receptors across the whole thalamocortical network, and their occurrence prior to seizure onset suggests that they might be of epileptogenic significance.

Published
2006

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