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3 results on '"unstable microsatellite repeats"'

1. Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy

Author

Géraldine Sicot, Laurent Servais, Diana M. Dinca, Axelle Leroy, Cynthia Prigogine, Fadia Medja, Sandra O. Braz, Aline Huguet-Lachon, Cerina Chhuon, Annie Nicole, Noëmy Gueriba, Ruan Oliveira, Bernard Dan, Denis Furling, Maurice S. Swanson, Ida Chiara Guerrera, Guy Cheron, Geneviève Gourdon, and Mário Gomes-Pereira

Subjects
myotonic dystrophy, unstable microsatellite repeats, brain, cerebellum, neurons, astrocytes, Bergmann glia, GLT1, glutamate, transgenic mice, ceftriaxone, Biology (General), QH301-705.5
Abstract

Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels.

Published
2017
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2. Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy.

Author

Sicot, Géraldine, Servais, Laurent, Dinca, Diana M., Leroy, Axelle, Prigogine, Cynthia, Medja, Fadia, Braz, Sandra O., Huguet-Lachon, Aline, Chhuon, Cerina, Nicole, Annie, Gueriba, Noëmy, Oliveira, Ruan, Dan, Bernard, Furling, Denis, Swanson, Maurice S., Guerrera, Ida Chiara, Cheron, Guy, Gourdon, Geneviève, and Gomes-Pereira, Mário

Abstract

Summary Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
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3. Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy

Author

Sicot, G, Servais, L, Dinca, DM, Leroy, A, Prigogine, C, Medja, F, Braz, SO, Huguet-Lachon, A, Chhuon, C, Nicole, A, Gueriba, N, Oliveira, R, Dan, B, Furling, D, Swanson, MS, Guerrera, IC, Cheron, G, Gourdon, G, Gomes-Pereira, M, Gomes-Pereira, Mario, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, BLANC - Anomalies précoces dans un modèle murin de la dystrophie myotonique de Steinert : un modèle de la forme congénitale ? - - MODELCDM2010 - ANR-10-BLAN-1121 - BLANC - VALID, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory of Neurophysiology and Biomechanics of Movement (LNBM), Université libre de Bruxelles (ULB), Université Sorbonne Paris Cité (USPC), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Florida [Gainesville] (UF), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-BLAN-1121,MODELCDM,Anomalies précoces dans un modèle murin de la dystrophie myotonique de Steinert : un modèle de la forme congénitale ?(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service of Clinical Trials and Databases, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Laboratory of Electrophysiology, University of Mons, 7000 Mons, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Bergmann glia, cerebellum, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, brain, Down-Regulation, neurons, Mice, Transgenic, glutamate, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, transgenic mice, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sciences de l'ingénieur, Article, Glutamate Plasma Membrane Transport Proteins, Mice, Purkinje Cells, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, lcsh:QH301-705.5, myotonic dystrophy, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, astrocytes, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, ceftriaxone, Disease Models, Animal, Excitatory Amino Acid Transporter 2, lcsh:Biology (General), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, nervous system, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], GLT1, unstable microsatellite repeats
Abstract

SUMMARY Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels., Graphical Abstract, In Brief Neural dysfunction in myotonic dystrophy is not fully understood. Using a transgenic mouse model of the disease, Sicot et al. find electrophysiological and motor evidence for cerebellar dysfunction in association with pronounced signs of RNA toxicity in Bergmann glia. Upregulation of a defective glial-specific glutamate transporter corrects cerebellum phenotypes.

Published
2017

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