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Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport
- Source :
- Nature Neuroscience. 9:1302-1311
- Publication Year :
- 2006
- Publisher :
- Springer Science and Business Media LLC, 2006.
-
Abstract
- Non-neuronal cells may be pivotal in neurodegenerative disease, but the mechanistic basis of this effect remains ill-defined. In the polyglutamine disease spinocerebellar ataxia type 7 (SCA7), Purkinje cells undergo non-cell-autonomous degeneration in transgenic mice. We considered the possibility that glial dysfunction leads to Purkinje cell degeneration, and generated mice that express ataxin-7 in Bergmann glia of the cerebellum with the Gfa2 promoter. Bergmann glia-specific expression of mutant ataxin-7 was sufficient to produce ataxia and neurodegeneration. Expression of the Bergmann glia-specific glutamate transporter GLAST was reduced in Gfa2-SCA7 mice and was associated with impaired glutamate transport in cultured Bergmann glia, cerebellar slices and cerebellar synaptosomes. Ultrastructural analysis of Purkinje cells revealed findings of dark cell degeneration consistent with excitotoxic injury. Our studies indicate that impairment of glutamate transport secondary to glial dysfunction contributes to SCA7 neurodegeneration, and suggest a similar role for glial dysfunction in other polyglutamine diseases and SCAs.
- Subjects :
- Male
Cerebellum
Ataxin 7
Amino Acid Transport System X-AG
Blotting, Western
Purkinje cell
Gene Expression
Glutamic Acid
Mice, Transgenic
Nerve Tissue Proteins
Transfection
Mice
Microscopy, Electron, Transmission
Glial Fibrillary Acidic Protein
medicine
Animals
Humans
Cells, Cultured
Aged
Ataxin-7
Behavior, Animal
Glial fibrillary acidic protein
biology
General Neuroscience
Neurodegeneration
Age Factors
Glutamate receptor
Brain
Neurodegenerative Diseases
medicine.disease
Immunohistochemistry
Mice, Inbred C57BL
medicine.anatomical_structure
Animals, Newborn
nervous system
Spinocerebellar ataxia
biology.protein
Neuroglia
Female
Neuroscience
Subjects
Details
- ISSN :
- 15461726 and 10976256
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Nature Neuroscience
- Accession number :
- edsair.doi.dedup.....668d5314242832629d7c4cc46176f63d