title: In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects.
abstract: 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.
authors.affiliation: CEA, Institute of Biomedical Imaging, Molecular Imaging Research Center, F-92265 Fontenay-aux-Roses, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Faideau
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.forename: Kerry
authors.initials: K
authors.lastname: Cormier
authors.forename: Richard
authors.initials: R
authors.lastname: Gilmore
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Welch
authors.forename: Gwennaelle
authors.initials: G
authors.lastname: Auregan
authors.forename: Noelle
authors.initials: N
authors.lastname: Dufour
authors.forename: Martine
authors.initials: M
authors.lastname: Guillermier
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: Gilles
authors.initials: G
authors.lastname: Bonvento
mesh_terms: D000368:Aged; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013997:Time Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D027322:Amino Acid Transport System X-AG; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005904:Glial Fibrillary Acidic Protein; D050505:Mutant Proteins; C121001:NR2B NMDA receptor; D010455:Peptides; C497929:Ppp1r1b protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C097188:polyglutamine; D018698:Glutamic Acid