Astrocytes are key but indirect contributors to the development of the symptomatology and pathophysiology of Huntington's disease.

Détails

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Etat: Serval
Version: Author's accepted manuscript
ID Serval
serval:BIB_CCF30D345F54
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Astrocytes are key but indirect contributors to the development of the symptomatology and pathophysiology of Huntington's disease.
Périodique
Glia
Auteur(s)
Meunier C., Merienne N., Jollé C., Déglon N., Pellerin L.
ISSN
1098-1136 (Electronic)
ISSN-L
0894-1491
Statut éditorial
Publié
Date de publication
11/2016
Peer-reviewed
Oui
Volume
64
Numéro
11
Pages
1841-1856
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Huntington's disease (HD) is a fatal neurodegenerative disease in which an early and selective vulnerability of striatal Spiny Projection Neurons is observed. However, several studies have highlighted the implication of glial cells, and in particular astrocytes, in the pathophysiological mechanisms of this disease. A better understanding of the respective contributions of neurons and astrocytes in HD is needed and would be important for the development of new therapeutic approaches. Today, no comparable in vivo models expressing the mutant HTT selectively in astrocytes or in neurons are available. In this study, we developed comparable cell-type specific mouse models expressing a fragment of Huntingtin specifically in neurons, astrocytes, or in both cell populations of the adult mouse basal ganglia circuit. This approach allowed us to characterize behavioral alterations occurring as soon as 4 weeks postinjection. Interestingly, less severe but significant behavioral alterations were also observed in the two cell-type specific models. We further showed that astrocytes are less affected by mHTT compared to neurons, in particular concerning mHTT aggregation. Additionally, a more indirect contribution of astrocytes compared to neurons was observed in several pathophysiological mechanisms such as astrogliosis and neuronal dysfunction. Finally, we showed that direct and indirect transcriptional alterations within the glial glutamatergic clearing system are caused by astrocytic and neuronal expression of mHTT, respectively. We anticipate that our study will help to better understand the contributions of astrocytes to HD and guide future therapeutic efforts. GLIA 2016;64:1841-1856.

Mots-clé
Animals, Astrocytes/metabolism, Astrocytes/pathology, Brain/pathology, Cyclophilin A/metabolism, Disease Models, Animal, Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism, Gene Expression Regulation/genetics, Glial Fibrillary Acidic Protein/metabolism, Glutamate-Ammonia Ligase/genetics, Glutamate-Ammonia Ligase/metabolism, Glutamic Acid/metabolism, Glutamine/metabolism, Humans, Huntingtin Protein/genetics, Huntingtin Protein/metabolism, Huntington Disease/complications, Huntington Disease/genetics, Huntington Disease/pathology, Locomotion/genetics, Locomotion/physiology, Mice, Mice, Transgenic, Mutation/genetics, Nerve Tissue Proteins/metabolism, Neurons/pathology, Nuclear Proteins/metabolism, adenoassociated viral vectors, glia, mouse model, polyglutamine expansion, striatum
Pubmed
Web of science
Open Access
Oui
Création de la notice
30/07/2016 12:55
Dernière modification de la notice
09/05/2019 1:22
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