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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.

References

  1. Clement, A.M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117 (2003).

    Article  CAS  Google Scholar 

  2. McGeer, P.L. et al. Microglia in degenerative neurological disease. Glia 7, 84–92 (1993).

    Article  CAS  Google Scholar 

  3. Raeber, A.J. et al. Astrocyte-specific expression of hamster prion protein (PrP) renders PrP knockout mice susceptible to hamster scrapie. EMBO J. 16, 6057–6065 (1997).

    Article  CAS  Google Scholar 

  4. Yazawa, I. et al. Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45, 847–859 (2005).

    Article  CAS  Google Scholar 

  5. Forman, M.S. et al. Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J. Neurosci. 25, 3539–3550 (2005).

    Article  CAS  Google Scholar 

  6. Voogd, J. & Glickstein, M. The anatomy of the cerebellum. Trends Neurosci. 21, 370–375 (1998).

    Article  CAS  Google Scholar 

  7. Taroni, F. & DiDonato, S. Pathways to motor incoordination: the inherited ataxias. Nat. Rev. Neurosci. 5, 641–655 (2004).

    Article  CAS  Google Scholar 

  8. Konigsmark, B.W. & Weiner, L.P. The olivopontocerebellar atrophies: a review. Medicine (Baltimore) 49, 227–241 (1970).

    Article  CAS  Google Scholar 

  9. Zoghbi, H.Y. & Orr, H.T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247 (2000).

    Article  CAS  Google Scholar 

  10. Garden, G.A. et al. Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice. J. Neurosci. 22, 4897–4905 (2002).

    Article  CAS  Google Scholar 

  11. La Spada, A.R. et al. Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron 31, 913–927 (2001).

    Article  CAS  Google Scholar 

  12. Borchelt, D.R. et al. A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet. Anal. 13, 159–163 (1996).

    Article  CAS  Google Scholar 

  13. Gu, X. et al. Pathological cell-cell interactions elicited by a neuropathogenic form of mutant huntingtin contribute to cortical pathogenesis in HD mice. Neuron 46, 433–444 (2005).

    Article  CAS  Google Scholar 

  14. Grosche, J. et al. Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat. Neurosci. 2, 139–143 (1999).

    Article  CAS  Google Scholar 

  15. Yamada, K. et al. Dynamic transformation of Bergmann glial fibers proceeds in correlation with dendritic outgrowth and synapse formation of cerebellar Purkinje cells. J. Comp. Neurol. 418, 106–120 (2000).

    Article  CAS  Google Scholar 

  16. Brenner, M., Kisseberth, W.C., Su, Y., Besnard, F. & Messing, A. GFAP promoter directs astrocyte-specific expression in transgenic mice. J. Neurosci. 14, 1030–1037 (1994).

    Article  CAS  Google Scholar 

  17. Brenner, M. & Messing, A. GFAP transgenic mice. Methods 10, 351–364 (1996).

    Article  CAS  Google Scholar 

  18. Strahlendorf, J.C., Brandon, T., Miles, R. & Strahlendorf, H.K. AMPA receptor-mediated alterations of intracellular calcium homeostasis in rat cerebellar Purkinje cells in vitro: correlates to dark cell degeneration. Neurochem. Res. 23, 1355–1362 (1998).

    Article  CAS  Google Scholar 

  19. Strahlendorf, J.C. & Strahlendorf, H.K. Enduring changes in Purkinje cell electrophysiology following transient exposure to AMPA: correlates to dark cell degeneration. Neurosci. Res. 33, 155–162 (1999).

    Article  CAS  Google Scholar 

  20. Leranth, C. & Hamori, J. “Dark” Purkinje cells of the cerebellar cortex. Acta Biol. Acad. Sci. Hung. 21, 405–419 (1970).

    CAS  PubMed  Google Scholar 

  21. Furuta, A., Rothstein, J.D. & Martin, L.J. Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J. Neurosci. 17, 8363–8375 (1997).

    Article  CAS  Google Scholar 

  22. Yoo, S.Y. et al. SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 37, 383–401 (2003).

    Article  CAS  Google Scholar 

  23. Cui, W., Allen, N.D., Skynner, M., Gusterson, B. & Clark, A.J. Inducible ablation of astrocytes shows that these cells are required for neuronal survival in the adult brain. Glia 34, 272–282 (2001).

    Article  CAS  Google Scholar 

  24. Fields, R.D. & Stevens-Graham, B. New insights into neuron-glia communication. Science 298, 556–562 (2002).

    Article  CAS  Google Scholar 

  25. Watase, K. et al. Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice. Eur. J. Neurosci. 10, 976–988 (1998).

    Article  CAS  Google Scholar 

  26. Huang, H. & Bordey, A. Glial glutamate transporters limit spillover activation of presynaptic NMDA receptors and influence synaptic inhibition of Purkinje neurons. J. Neurosci. 24, 5659–5669 (2004).

    Article  CAS  Google Scholar 

  27. Arriza, J.L. et al. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J. Neurosci. 14, 5559–5569 (1994).

    Article  CAS  Google Scholar 

  28. Shin, J.Y. et al. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 171, 1001–1012 (2005).

    Article  CAS  Google Scholar 

  29. Iino, M. et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001).

    Article  CAS  Google Scholar 

  30. Gong, Y.H., Parsadanian, A.S., Andreeva, A., Snider, W.D. & Elliott, J.L. Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J. Neurosci. 20, 660–665 (2000).

    Article  CAS  Google Scholar 

  31. Yvert, G. et al. Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice. Hum. Mol. Genet. 9, 2491–2506 (2000).

    Article  CAS  Google Scholar 

  32. Probst-Cousin, S. et al. Spinocerebellar ataxia type 2 with glial cell cytoplasmic inclusions. J. Neurol. Neurosurg. Psychiatry 75, 503–505 (2004).

    Article  CAS  Google Scholar 

  33. Palhan, V.B. et al. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc. Natl. Acad. Sci. USA 102, 8472–8477 (2005).

    Article  CAS  Google Scholar 

  34. Helmlinger, D. et al. Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum. Mol. Genet. 13, 1257–1265 (2004).

    Article  CAS  Google Scholar 

  35. La Spada, A.R. & Taylor, J.P. Polyglutamines placed into context. Neuron 38, 681–684 (2003).

    Article  CAS  Google Scholar 

  36. Robinson, M.B. & Dowd, L.A. Heterogeneity and functional properties of subtypes of sodium-dependent glutamate transporters in the mammalian central nervous system. Adv. Pharmacol. 37, 69–115 (1997).

    Article  CAS  Google Scholar 

  37. Gegelashvili, G. et al. Glutamate receptor agonists up-regulate glutamate transporter GLAST in astrocytes. Neuroreport 8, 261–265 (1996).

    Article  CAS  Google Scholar 

  38. Duan, S., Anderson, C.M., Stein, B.A. & Swanson, R.A. Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J. Neurosci. 19, 10193–10200 (1999).

    Article  CAS  Google Scholar 

  39. Lehre, K.P. & Danbolt, N.C. The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J. Neurosci. 18, 8751–8757 (1998).

    Article  CAS  Google Scholar 

  40. Dehnes, Y. et al. The glutamate transporter EAAT4 in rat cerebellar Purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J. Neurosci. 18, 3606–3619 (1998).

    Article  CAS  Google Scholar 

  41. Lin, X., Antalffy, B., Kang, D., Orr, H.T. & Zoghbi, H.Y. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat. Neurosci. 3, 157–163 (2000).

    Article  CAS  Google Scholar 

  42. Serra, H.G. et al. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum. Mol. Genet. 13, 2535–2543 (2004).

    Article  CAS  Google Scholar 

  43. Ikeda, Y. et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat. Genet. 38, 184–190 (2006).

    Article  CAS  Google Scholar 

  44. Rothstein, J.D., Van Kammen, M., Levey, A.I., Martin, L.J. & Kuncl, R.W. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. 38, 73–84 (1995).

    Article  CAS  Google Scholar 

  45. Rothstein, J.D. et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005).

    Article  CAS  Google Scholar 

  46. Lin, C.H. et al. Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum. Mol. Genet. 10, 137–144 (2001).

    Article  CAS  Google Scholar 

  47. Ortega, A., Eshhar, N. & Teichberg, V.I. Properties of kainate receptor/channels on cultured Bergmann glia. Neuroscience 41, 335–349 (1991).

    Article  CAS  Google Scholar 

  48. Shimada, F. et al. The neuroprotective agent MS-153 stimulates glutamate uptake. Eur. J. Pharmacol. 386, 263–270 (1999).

    Article  CAS  Google Scholar 

  49. Lievens, J.C. et al. Impaired glutamate uptake in the R6 Huntington's disease transgenic mice. Neurobiol. Dis. 8, 807–821 (2001).

    Article  CAS  Google Scholar 

Download references

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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