title: Astrocytes are key but indirect contributors to the development of the symptomatology and pathophysiology of Huntington's disease.
abstract: 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.
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Cécile
authors.initials: C
authors.lastname: Meunier
authors.affiliation: Department of Clinical Neurosciences, Laboratory of Cellular and Molecular Neurotherapies (LCMN), Lausanne University Hospital, Lausanne, Switzerland.|Neuroscience Research Center (CRN), LCMN, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Merienne
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Jollé
authors.affiliation: Department of Clinical Neurosciences, Laboratory of Cellular and Molecular Neurotherapies (LCMN), Lausanne University Hospital, Lausanne, Switzerland.|Neuroscience Research Center (CRN), LCMN, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland. Luc.Pellerin@unil.ch.
authors.forename: Luc
authors.initials: L
authors.lastname: Pellerin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D021984:Cyclophilin A / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D008124:Locomotion / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005904:Glial Fibrillary Acidic Protein; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D005973:Glutamine; D018698:Glutamic Acid; D021984:Cyclophilin A; D005974:Glutamate-Ammonia Ligase
keywords: adenoassociated viral vectors; glia; mouse model; polyglutamine expansion; striatum