Upregulation of brain utrophin does not rescue behavioral alterations in dystrophin-deficient mice
| Autor: | Pascale M. Le Blanc, Sabine De La Porte, Dominique Mornet, Cyrille Vaillend, Serge Laroche, Caroline Perronnet, Carine Chagneau, Nathalie Samson-Desvignes |
|---|---|
| Přispěvatelé: | Centre de Neurosciences Paris-Sud (CNPS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie de l'apprentissage, de la mémoire et de la communication (NAMC), Neurobiologie & Développement (N&D), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Arginine
Utrophin Duchenne muscular dystrophy animal diseases Endogeny MESH: Butyrates MESH: Mice Knockout MESH: Muscular Dystrophy Animal Dystrophin Mice 0302 clinical medicine MESH: Up-Regulation MESH: Animals Muscular dystrophy Genetics (clinical) Mice Knockout 0303 health sciences MESH: Mice Inbred mdx MESH: Arginine Brain General Medicine musculoskeletal system Phenotype Up-Regulation Butyrates [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Biology 03 medical and health sciences MESH: Utrophin MESH: Brain Downregulation and upregulation MESH: Dystrophin Genetics medicine MESH: Muscular Dystrophy Duchenne Animals RNA Messenger Molecular Biology MESH: Mice 030304 developmental biology MESH: RNA Messenger Muscular Dystrophy Animal medicine.disease Muscular Dystrophy Duchenne Immunology biology.protein Mice Inbred mdx Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2012, 21 (10), pp.2263-76. ⟨10.1093/hmg/dds047⟩ |
| ISSN: | 0964-6906 1460-2083 |
| DOI: | 10.1093/hmg/dds047⟩ |
| Popis: | International audience; Dystrophin, the protein responsible for X-linked Duchenne muscular dystrophy (DMD), is normally expressed in both muscle and brain, which explains that its loss also leads to cognitive deficits. The utrophin protein, an autosomal homolog, is a natural candidate for dystrophin replacement in patients. Pharmacological upregulation of endogenous utrophin improves muscle physiology in dystrophin-deficient mdx mice, and represents a potential therapeutic tool that has the advantage of allowing delivery to various organs following peripheral injections. Whether this could alleviate cognitive deficits, however, has not been explored. Here, we first investigated basal expression of all utrophins and dystrophins in the brain of mdx mice and found no evidence for spontaneous compensation by utrophins. Then, we show that systemic chronic, spaced injections of arginine butyrate (AB) alleviate muscle alterations and upregulate utrophin expression in the adult brain of mdx mice. AB selectively upregulated brain utrophin Up395, while reducing expression of Up113 and Up71. This, however, was not associated with a significant improvement of behavioral functions typically affected in mdx mice, which include exploration, emotional reactivity, spatial and fear memories. We suggest that AB did not overcome behavioral and cognitive dysfunctions because the regional and cellular expression of utrophins did not coincide with dystrophin expression in untreated mice, nor did it in AB-treated mice. While treatments based on the modulation of utrophin may alleviate DMD phenotypes in certain organs and tissues that coexpress dystrophins and utrophins in the same cells, improvement of cognitive functions would likely require acting on specific dystrophin-dependent mechanisms. |
| Databáze: | OpenAIRE |
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