Nature Neuroscience
- 9, 1302 - 1311 (2006)
Published online: 27 August 2006; | doi:10.1038/nn1750
Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transportSara K Custer1, Gwenn A Garden2, 3, Nishi Gill2, Udo Rueb4, Randell T Libby1, Christian Schultz4, Stephan J Guyenet1, Thomas Deller4, Lesnick E Westrum5, 7, Bryce L Sopher1 & Albert R La Spada1, 2, 3, 61
Department of Laboratory Medicine, University of Washington Medical Center, Seattle, Washington 98195, USA. 2
Department of Neurology (Neurogenetics), University of Washington Medical Center, Seattle, Washington 98195, USA. 3
Center for Neurogenetics and Neurotherapeutics, University of Washington Medical Center, Seattle, Washington 98195, USA. 4
Department of Clinical Neuroanatomy, J.W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany. 5
Department of Neurosurgery, University of Washington Medical Center, Seattle, Washington 98195, USA. 6
Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, Washington 98195, USA. 7
Deceased.
Correspondence should be addressed to Albert R La Spada laspada@u.washington.edu 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.
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