serval:BIB_CCF30D345F54
Astrocytes are key but indirect contributors to the development of the symptomatology and pathophysiology of Huntington's disease.
10.1002/glia.23022
000386751600003
27442486
Meunier
C.
author
Merienne
N.
author
Jollé
C.
author
Déglon
N.
author
Pellerin
L.
author
article
2016-11
Glia
1098-1136
0894-1491
journal
64
11
1841-1856
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.
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
eng
60_published
true
peer-reviewed
Publication types: Journal Article
Publication Status: ppublish
University of Lausanne
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