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Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1

Nature Neuroscience volume 3, pages 157–163 (2000)Cite this article

Abstract

The expansion of an unstable CAG repeat causes spinocerebellar ataxia type 1 (SCA1) and several other neurodegenerative diseases. How polyglutamine expansions render the resulting proteins toxic to neurons, however, remains elusive. Hypothesizing that long polyglutamine tracts alter gene expression, we found certain neuronal genes involved in signal transduction and calcium homeostasis sequentially downregulated in SCA1 mice. These genes were abundant in Purkinje cells, the primary site of SCA1 pathogenesis; moreover, their downregulation was mediated by expanded ataxin-1 and occured before detectable pathology. Similar downregulation occurred in SCA1 human tissues. Altered gene expression may be the earliest mediator of polyglutamine toxicity.

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Figure 1: PCCMT expression was specifically reduced in SCA1 mice.
Figure 2: PCCMT mRNA expression in mouse and human brain.
Figure 3: IP3R1 and SERCA2 expression is reduced in SCA1 mice and patient brain tissues.
Figure 4: Downregulation of type 1 inositol polyphosphate 5-phosphatase, TRP3 and EAAT4 in SCA1 mice.
Figure 5: Mutant ataxin-1 does not affect expression of all Purkinje cell-specific genes.
Figure 6: Upregulation of EB22/4, a mouse homolog of human α1-ACT.

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Acknowledgements

The authors thank A. Beaudet for providing the Ube3a null mice, M. Philips at New York University School of Medicine and K. Tanaka at the National Institute of Neuroscience in Japan for providing the anti-PCCMT and anti-EAAT4 antibodies, H. J. Bellen for reading the manuscript and V. Brandt for comments. This work was supported by grants NS27699 and NS22920 from the National Institutes of Health (to H.Y.Z. and H.T.O.) and by the core facilities of the Baylor College of Medicine Mental Retardation Research Center. X. Lin is an Associate and H. Zoghbi an Investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Xi Lin, Dongcheul Kang & Huda Y. Zoghbi

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston , 77030, Texas, USA

    Xi Lin, Dongcheul Kang & Huda Y. Zoghbi

  3. Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Barbara Antalffy

  4. Department of Laboratory Medicine and Pathology, Institute of Human Genetics, University of Minnesota, Harvard Street at East River Rd., Minneapolis, 55455, Minnesota, USA

    Harry T. Orr

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Correspondence to Huda Y. Zoghbi.

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Lin, X., Antalffy, B., Kang, D. et al. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci 3, 157–163 (2000). https://doi.org/10.1038/72101

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