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3 results on '"AMX-19-IET-004"'

1. NAPB and developmental and epileptic encephalopathy: Description of the electroclinical profile associated with a novel pathogenic variant

Author

Cécile Mignon‐Ravix, Florence Riccardi, Géraldine Daquin, Pierre Cacciagli, Sylvie Lamoureux‐Toth, Laurent Villard, Nathalie Villeneuve, Florence Molinari, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurophysiologie clinique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Henri Duffaut (Avignon), Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], and A*Midex : AMX-19-IET-004

Subjects
Electroencephalogram, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Seizures, SNARE, [SCCO.NEUR]Cognitive science/Neuroscience, NAPB, Neurology (clinical), SNAP, Whole Exome Sequencing, Developmental and Epileptic Encephalopathies
Abstract

International audience; Developmental and epileptic encephalopathies (DEE) are a group of neurodevelopmental disorders characterized by epileptic seizures associated with developmental delay or regression. DEE are genetically heterogeneous, and the proteins involved play roles in multiple pathways such as synaptic transmission, metabolism, neuronal development or maturation, transcriptional regulation, and intracellular trafficking. We performed whole exome sequencing on a consanguineous family with three children presenting an early onset (

Published
2023

2. 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

3. Correction: Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

Author

Xavier Caubit, Paolo Gubellini, Pierre L. Roubertoux, Michèle Carlier, Jordan Molitor, Dorian Chabbert, Mehdi Metwaly, Pascal Salin, Ahmed Fatmi, Yasmine Belaidouni, Lucie Brosse, Lydia Kerkerian-Le Goff, Laurent Fasano, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de psychologie cognitive (LPC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), This work has received support from the French government under the Programme 'Investissements d’Avenir', Initiative d’Excellence d’Aix-Marseille Université via A*Midex funding (NeuroMarseille Institute, AMX-19-IET-004, MarMaRa Institute, AMX-19-IET-007). We wish to thank the IBDM mouse facility. This work was supported by the Fédération pour la Recherche sur le Cerveau (FRC) (to L.F.), the Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille University. D.C. and J.M. were supported by PhD grants from the MESRI (Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-17-EURE-0029,nEURo*AMU,Marseille NeuroSchool, une formation d'excellence(2017), ANR-17-CE16-0030,TSHZ3inASD,Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique(2017), Gubellini, Paolo, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Marseille NeuroSchool, une formation d'excellence - - nEURo*AMU2017 - ANR-17-EURE-0029 - EURE - VALID, and Rôle de TSHZ3 dans le développement et la fonction de systèmes neuronaux impliqués dans les troubles du spectre autistique - - TSHZ3inASD2017 - ANR-17-CE16-0030 - AAPG2017 - VALID

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Biological Psychiatry
Abstract

International audience; We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. In the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABAergic interneurons, but not in cholinergic interneurons or glial cells. In the striatum, TSHZ3 is expressed in all SCINs, while its expression is absent or partial in the other main brain cholinergic systems. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3 flox/flox with Emx1-Cre (Emx1-cKO) or Chat-Cre (Chat-cKO) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and impaired plasticity at corticostriatal synapses, with neither cortical neuron loss nor abnormal layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.

Published
2022

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