Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy
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,
Mário Gomes-Pereira
Affiliations
Géraldine Sicot
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France
Laurent Servais
Institut I-Motion, Hôpital Armand Trousseau, 75012 Paris, France
Diana M. Dinca
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France
Axelle Leroy
Laboratory of Neurophysiology and Movement Biomechanics, Université Libre de Bruxelles, 1050 Brussels, Belgium
Cynthia Prigogine
Laboratory of Neurophysiology and Movement Biomechanics, Université Libre de Bruxelles, 1050 Brussels, Belgium
Fadia Medja
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France
Sandra O. Braz
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France
Aline Huguet-Lachon
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France
Cerina Chhuon
Proteomics Platform 3P5-Necker, Université Paris Descartes-Structure Fédérative de Recherche Necker, Inserm US24/CNRS UMS3633, 75014 Paris, France
Annie Nicole
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France
Noëmy Gueriba
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France
Ruan Oliveira
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA
Bernard Dan
Laboratory of Neurophysiology and Movement Biomechanics, Université Libre de Bruxelles, 1050 Brussels, Belgium
Denis Furling
Sorbonne Universités UPMC Université Paris 06, Inserm, Centre de Recherche en Myologie UMRS974, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France
Maurice S. Swanson
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA
Ida Chiara Guerrera
Proteomics Platform 3P5-Necker, Université Paris Descartes-Structure Fédérative de Recherche Necker, Inserm US24/CNRS UMS3633, 75014 Paris, France
Guy Cheron
Laboratory of Neurophysiology and Movement Biomechanics, Université Libre de Bruxelles, 1050 Brussels, Belgium
Geneviève Gourdon
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France
Mário Gomes-Pereira
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France
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.
