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miR-19, miR-101 and miR-130 co-regulate ATXN1 levels to potentially modulate SCA1 pathogenesis

Nature Neuroscience volume 11, pages 1137–1139 (2008)Cite this article

Abstract

Spinocerebellar ataxia type 1 is caused by expansion of a translated CAG repeat in ataxin1 (ATXN1). The level of the polyglutamine-expanded protein is one of the factors that contributes to disease severity. Here we found that miR-19, miR-101 and miR-130 co-regulate ataxin1 levels and that their inhibition enhanced the cytotoxicity of polyglutamine-expanded ATXN1 in human cells. We provide a new candidate mechanism for modulating the pathogenesis of neurodegenerative diseases sensitive to protein dosage.

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Figure 1: miR-19, miR-101 and miR-130 regulate ATXN1 levels.
Figure 2: Purkinje cell expression of miR-19, miR-101 and miR-130.
Figure 3: Inhibition of miRNA-mediated post-transcriptional regulation of polyQ-expanded ATXN1 causes more severe cytotoxicity in HEK293T cells.

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Acknowledgements

We thank N. Ao, Y. Liu and A. Liang of the Baylor College of Medicine In Situ Hybridization core for technical assistance and V.N. Kim and members of the Zoghbi laboratory for helpful discussions and comments on the manuscript. This research was supported by US National Institutes of Health grants NS27699 and HD24064 to H.Y.Z. and NS22920 to H.T.O. H.Y.Z. is an investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, Texas, USA

    Yoontae Lee, Rodney C Samaco & Huda Y Zoghbi

  2. Department of Neuroscience, Baylor College of Medicine, Houston, 77030, Texas, USA

    Jennifer R Gatchel & Huda Y Zoghbi

  3. Departments of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Christina Thaller & Huda Y Zoghbi

  4. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, 77030, Texas, USA

    Yoontae Lee & Huda Y Zoghbi

  5. Department of Biochemistry, Department of Laboratory Medicine and Pathology, Institute of Human Genetics, Biophysics and Molecular Biology, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Harry T Orr

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  1. Yoontae Lee
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  2. Rodney C Samaco
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  4. Christina Thaller
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  6. Huda Y Zoghbi
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Contributions

Y.L. and H.Y.Z. designed the experiments. Y.L. carried out the majority of the experiments, with the exception of those comparing SCA1[82Q]Tg/+ and SCA1[82Q]Tg/Tg mice in Supplementary Figure 1 (J.R.G. and R.C.S.) and the RNA in situ hybridization experiments in Figure 2 (C.T.). Data analyses and interpretation were conducted by Y.L., H.T.O. and H.Y.Z. Y.L. and H.Y.Z. wrote the paper.

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Correspondence to Huda Y Zoghbi.

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Supplementary Figures 1–8 and Supplementary Methods (PDF 7176 kb)

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Lee, Y., Samaco, R., Gatchel, J. et al. miR-19, miR-101 and miR-130 co-regulate ATXN1 levels to potentially modulate SCA1 pathogenesis. Nat Neurosci 11, 1137–1139 (2008). https://doi.org/10.1038/nn.2183

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