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Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport

Nature Neuroscience volume 9, pages 1302–1311 (2006)Cite this article

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.

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Figure 1: Purkinje cell degeneration and Bergmann glia pathology in SCA7.
Figure 2: Generation and characterization of Gfa2-SCA7 transgenic mice.
Figure 3: Gfa2-SCA7-92Q mice develop a neurological phenotype.
Figure 4: Purkinje cell degeneration in Gfa2-SCA7 92Q mice.
Figure 5: Bergmann glia pathology in SCA7.
Figure 6: Reduced GLAST transporter function in Gfa2-SCA7-92Q mice.
Figure 7: Glutamate uptake abnormalities in Gfa2-SCA7-92Q mice.
Figure 8: Dark cell degeneration of Gfa2-SCA7-92Q Purkinje cells.

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Acknowledgements

We would like to thank A.H. Koeppen (VA Medical Center, Albany, New York) with support from the National Ataxia Foundation for brain sections, E. Brunt for clinical assessment of patients, J. Huang, D.E. Possin, H. Korff, B. Meseck-Selchow, S. Baccam, V. Damian, C. Plata, A.C. Smith and B. Wang for technical assistance, and H. Zoghbi and J. Gatchel-Rose for providing the SCA7-266Q knock-in mice. This work was supported by funding from the US National Institutes of Health (EY14061 to A.R.L., P30 HD02774 from the National Institute of Child Health and Human Development, a National Organization for Rare Disease (NORD) grant to G.A.G. and a Neurobiology Predoctoral training grant to S.K.C.), the Deutsche Forschungsgemeinschaft (RU 1215/1-1), the Deutsche Heredo-Ataxie-Gesellschaft (DHAG), the ADCA-Vereniging Nederland and the Bernd Fink-Stiftung (Düsseldorf, Germany). A.R.L. is a recipient of a Paul Beeson Physician Faculty Scholar in Aging Research award from the American Foundation for Aging Research (AFAR).

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  1. Lesnick E Westrum: Deceased.

Authors and Affiliations

  1. Department of Laboratory Medicine, University of Washington Medical Center, Seattle, 98195, Washington, USA

    Sara K Custer, Randell T Libby, Stephan J Guyenet, Bryce L Sopher & Albert R La Spada

  2. Department of Neurology (Neurogenetics), University of Washington Medical Center, Seattle, 98195, Washington, USA

    Gwenn A Garden, Nishi Gill & Albert R La Spada

  3. Center for Neurogenetics and Neurotherapeutics, University of Washington Medical Center, Seattle, 98195, Washington, USA

    Gwenn A Garden & Albert R La Spada

  4. Department of Clinical Neuroanatomy, J.W. Goethe-University, Theodor-Stern-Kai 7, Frankfurt/Main, D-60590, Germany

    Udo Rueb, Christian Schultz & Thomas Deller

  5. Department of Neurosurgery, University of Washington Medical Center, Seattle, 98195, Washington, USA

    Lesnick E Westrum

  6. Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, 98195, Washington, USA

    Albert R La Spada

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Contributions

S.K.C. and B.L.S. conducted the Gfa2 transgenic studies and glutamate transporter studies. G.A.G. performed the histology analysis. G.A.G., N.G. and L.E.W. performed the ultrastructural analysis. R.T.L. and S.J.G. carried out the expression analysis. U.R., C.S. and T.D. conducted the histology analysis. A.R.L.S. directed all studies.

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Correspondence to Albert R La Spada.

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Supplementary information

Supplementary Fig. 1

Bergmann glia cell bodies ensheath Purkinje cells. (PDF 138 kb)

Supplementary Fig. 2

Validation of Gfa2-SCA7 expression constructs in Bergmann glia and in transgenic mice. (PDF 7540 kb)

Supplementary Fig. 3

Morphological criteria for ultrastructural assessment of Purkinje cell dendrites. (PDF 181 kb)

Supplementary Fig. 4

PrP-SCA7-92Q mice display Bergmann glia pathology. (PDF 622 kb)

Supplementary Fig. 5

Dramatic degeneration of Bergmann glia in the high-expressing Gfa2-SCA7-92Q line. (PDF 4705 kb)

Supplementary Fig. 6

Western blot analysis of GLAST and GLT-1 protein expression in Gfa2-SCA7 transgenic mice at various ages. (PDF 627 kb)

Supplementary Fig. 7

PrP-SCA7-92Q Bergmann glia display reduced GLAST levels. (PDF 43 kb)

Supplementary Methods (PDF 155 kb)

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Custer, S., Garden, G., Gill, N. et al. Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat Neurosci 9, 1302–1311 (2006). https://doi.org/10.1038/nn1750

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