Rescue of a dystrophin-like protein by exon skipping in vivo restores GABAA-receptor clustering in the hippocampus of the mdx mouse
| Autor: | Olivier Danos, Carole Gruszczynski, Luis Garcia, Cyrille Vaillend, Carine Ros, Caroline Perronnet, Elise Peltekian, Aurélie Goyenvalle, Serge Laroche |
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| Přispěvatelé: | Mécanismes cellulaires et moléculaires de la plasticité et de la mémoire, Centre de Neurosciences Paris-Sud (CNPS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Thérapie des maladies du muscle strié, 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 de Neurosciences Paris-Sud ( CNPS ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
MESH : Dystrophin
Male mdx mouse MESH: Hippocampus Duchenne muscular dystrophy MESH : Immunohistochemistry [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology MESH : Blotting Western MESH : Mice Inbred mdx Hippocampal formation MESH : Hippocampus Hippocampus Polymerase Chain Reaction Dystrophin [ SDV.NEU.SC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences Mice 0302 clinical medicine MESH : Exons Drug Discovery MESH : Female MESH: Animals Muscular dystrophy MESH : Polymerase Chain Reaction MESH: Receptors GABA-A 0303 health sciences [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior MESH: Mice Inbred mdx [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences Exons Immunohistochemistry Cell biology [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Molecular Medicine Female Original Article musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities MESH : Male Blotting Western MESH : Mice Inbred C57BL Biology [ SDV.NEU.PC ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior 03 medical and health sciences MESH: Dystrophin MESH: Mice Inbred C57BL Utrophin MESH : Mice medicine Genetics MESH: Muscular Dystrophy Duchenne Animals MESH: Blotting Western Molecular Biology MESH: Mice 030304 developmental biology Pharmacology MESH : Receptors GABA-A MESH: Polymerase Chain Reaction MESH: Immunohistochemistry medicine.disease Receptors GABA-A Molecular biology Exon skipping MESH: Male Mice Inbred C57BL Muscular Dystrophy Duchenne Synaptic plasticity biology.protein Mice Inbred mdx MESH : Animals MESH: Exons MESH : Muscular Dystrophy Duchenne MESH: Female 030217 neurology & neurosurgery |
| Zdroj: | Molecular Therapy Molecular Therapy, Cell Press, 2010, 18 (9), pp.1683-8. ⟨10.1038/mt.2010.134⟩ Molecular Therapy, Nature Publishing Group, 2010, 18 (9), pp.1683-8. 〈10.1038/mt.2010.134〉 Molecular Therapy, 2010, 18 (9), pp.1683-8. ⟨10.1038/mt.2010.134⟩ Molecular Therapy, Nature Publishing Group, 2010, 18 (9), pp.1683-8. ⟨10.1038/mt.2010.134⟩ |
| ISSN: | 1525-0016 1525-0024 |
| DOI: | 10.1038/mt.2010.134⟩ |
| Popis: | International audience; Dystrophin, the cytoskeletal protein whose defect is responsible for Duchenne muscular dystrophy (DMD), is normally expressed in both muscles and brain. Genetic loss of brain dystrophin in the mdx mouse model of DMD reduces the capacity for type A gamma-aminobutyric acid (GABA(A))-receptor clustering in central inhibitory synapses, which is thought to be a main molecular defect leading to brain and cognitive alterations in this syndrome. U7 small nuclear RNAs modified to encode antisense sequences and expressed from recombinant adeno-associated viral (rAAV) vectors have proven efficient after intramuscular injection to induce skipping of the mutated exon 23 and rescue expression of a functional dystrophin-like product in muscle tissues of mdx mice in vivo. Here, we report that intrahippocampal injection of a single dose of rAAV2/1-U7 can rescue substantial levels of brain dystrophin expression (15-25%) in mdx mice for months. This is sufficient to completely restore GABA(A)-receptor clustering in pyramidal and dendritic layers of CA1 hippocampus, suggesting exon-skipping strategies offer the prospect to investigate and correct both brain and muscle alterations in DMD. This provides new evidence that in the adult brain dystrophin is critical for the control of GABA(A)-receptor clustering, which may have an important role in activity-dependent synaptic plasticity in hippocampal circuits. |
| Databáze: | OpenAIRE |
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