In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects

• Published in: Human molecular genetics Vol. 19; no. 15; pp. 3053 - 3067
• Main Authors: Faideau, Mathilde, Kim, Jinho, Cormier, Kerry, Gilmore, Richard, Welch, Mackenzie, Auregan, Gwennaelle, Dufour, Noelle, Guillermier, Martine, Brouillet, Emmanuel, Hantraye, Philippe, Déglon, Nicole, Ferrante, Robert J., Bonvento, Gilles
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.08.2010
• Subjects: Aged; Amino Acid Transport System X-AG - metabolism; Animals; Astrocytes - metabolism; Astrocytes - pathology; Biological and medical sciences; Biological Transport; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine and cAMP-Regulated Phosphoprotein 32 - metabolism; Down-Regulation; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Glial Fibrillary Acidic Protein - metabolism; Glutamic Acid - metabolism; Humans; Huntington Disease - metabolism; Huntington Disease - pathology; Lentivirus - genetics; Medical sciences; Mice; Middle Aged; Molecular and cellular biology; Mutant Proteins - metabolism; Neostriatum - metabolism; Neostriatum - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Peptides - metabolism; Phenotype; Receptors, N-Methyl-D-Aspartate - metabolism; Serotonin Plasma Membrane Transport Proteins - metabolism; Time Factors; Trinucleotide Repeat Expansion - genetics; Nervous system diseases; Correlation; Huntingtin; Neuroglia; Rodentia; Huntington disease; Central nervous system; Astrocyte; Glutamate; Genetic disease; Cerebral disorder; In vivo; Vertebrata; Mammalia; Mouse; Central nervous system disease; Excitatory aminoacid; Neurotransmitter; Genetics; Degenerative disease; Extrapyramidal syndrome
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddq212

Huntington's disease (HD) is a neurodegenerative disorder previously thought to be of primary neuronal origin, despite ubiquitous expression of mutant huntingtin (mHtt). We tested the hypothesis that mHtt expressed in astrocytes may contribute to the pathogenesis of HD. To better understand the contribution of astrocytes in HD in vivo, we developed a novel mouse model using lentiviral vectors that results in selective expression of mHtt into striatal astrocytes. Astrocytes expressing mHtt developed a progressive phenotype of reactive astrocytes that was characterized by a marked decreased expression of both glutamate transporters, GLAST and GLT-1, and of glutamate uptake. These effects were associated with neuronal dysfunction, as observed by a reduction in DARPP-32 and NR2B expression. Parallel studies in brain samples from HD subjects revealed early glial fibrillary acidic protein expression in striatal astrocytes from Grade 0 HD cases. Astrogliosis was associated with morphological changes that increased with severity of disease, from Grades 0 through 4 and was more prominent in the putamen. Combined immunofluorescence showed co-localization of mHtt in astrocytes in all striatal HD specimens, inclusive of Grade 0 HD. Consistent with the findings from experimental mice, there was a significant grade-dependent decrease in striatal GLT-1 expression from HD subjects. These findings suggest that the presence of mHtt in astrocytes alters glial glutamate transport capacity early in the disease process and may contribute to HD pathogenesis.