title: Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport.
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.
authors.affiliation: Department of Laboratory Medicine, University of Washington Medical Center, Seattle, Washington 98195, USA.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Custer
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
authors.forename: Nishi
authors.initials: N
authors.lastname: Gill
authors.forename: Udo
authors.initials: U
authors.lastname: Rueb
authors.forename: Randell T
authors.initials: RT
authors.lastname: Libby
authors.forename: Christian
authors.initials: C
authors.lastname: Schultz
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Guyenet
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.forename: Lesnick E
authors.initials: LE
authors.lastname: Westrum
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000367:Age Factors; D000368:Aged; D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D000067719:Ataxin-7; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009457:Neuroglia / Q000378:metabolism* / Q000648:ultrastructure; D014162:Transfection / Q000379:methods
chemical_list: C000593829:ATXN7 protein, human; D027322:Amino Acid Transport System X-AG; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D018698:Glutamic Acid