In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects
| Autor: | Jinho Kim, Mackenzie Welch, Robert J. Ferrante, Emmanuel Brouillet, Noelle Dufour, Philippe Hantraye, Nicole Déglon, Richard Gilmore, Gilles Bonvento, Mathilde Faideau, Kerry Cormier, Martine Guillermier, Gwennaelle Auregan |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Time Factors
Huntingtin Amino Acid Transport System X-AG Fluorescent Antibody Technique Mice 0302 clinical medicine Genetics (clinical) Neurons Serotonin Plasma Membrane Transport Proteins 0303 health sciences Glial fibrillary acidic protein Glutamate receptor Articles General Medicine Middle Aged 3. Good health Astrogliosis Cell biology Huntington Disease Phenotype medicine.anatomical_structure Biochemistry Neuroglia Astrocyte Dopamine and cAMP-Regulated Phosphoprotein 32 Central nervous system Down-Regulation Glutamic Acid Biology Receptors N-Methyl-D-Aspartate 03 medical and health sciences Huntington's disease Glial Fibrillary Acidic Protein Genetics medicine Animals Humans Molecular Biology Aged 030304 developmental biology Lentivirus Biological Transport medicine.disease Neostriatum nervous system Astrocytes biology.protein Mutant Proteins Peptides Trinucleotide Repeat Expansion 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics; Vol 19 Human Molecular Genetics |
| ISSN: | 1460-2083 |
| DOI: | 10.1093/hmg/ddq212 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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