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Modeling Pathogenesis of Huntington’s Disease with Inducible Neuroprogenitor Cells

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Abstract

Huntington’s disease (HD) is caused by an abnormal expansion of CAG trinucleotide repeats encoding polyglutamine (polyQ) in the first exon of the huntingtin (htt) gene. Despite considerable efforts, the pathogenesis of HD remains largely unclear due to a paucity of models that can reliably reproduce the pathological characteristics of HD. Here, we report a neuronal cell model of HD using the previously established tetracycline regulated rat neuroprogenitor cell line, HC2S2. Stable expression of enhanced green fluorescence protein tagged htt exon 1 (referred to as 28Q and 74Q, respectively) in the HC2S2 cells did not affect rapid neuronal differentiation. However, compared to the cells expressing wild type htt, the cell line expressing mutant htt showed an increase in time-dependent cell death and neuritic degeneration, and displayed increased vulnerability to oxidative stress. Increased protein aggregation during the process of neuronal aging or when the cells were exposed to oxidative stress reagents was detected in the cell line expressing 74Q but not in its counterpart. These results suggest that the neuroprogenitor cell lines mimic the major neuropathological characteristics of HD and may provide a useful tool for studying the neuropathogenesis of HD and for high throughput screening of therapeutic compounds.

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Acknowledgments

We would like to thank Dr. Robin Miskimins for critically reading the manuscript, Dr. Fred H. Gage for providing the HC2S2 neuronal cell line, Dr. David C. Rubinsztein for providing EGFP-htt constructs, Drs. Joyce Keifer and Fran Day at the South Dakota Imaging Core Facility (supported by NIH P20 RR 015567, which is designated as a Center of Biomedical Research Excellence (COBRE) to Dr. Joyce Keifer) for help in confocal and fluorescence microscopy, and Drs. Huabo Su, and Ms. Lili Guo for providing assistance in fluorescence microscopy. We are also grateful to Dr. Kathleen Eyster and Ms. Sandy Bradley at the South Dakota Genomics Core Facility (supported by NIH INBRE 2 P20 RR016479) for their assistance in using the Nucleofector device. This study was supported by Start-up Funds from the University of South Dakota, a Competitive Research Grant Award of the South Dakota Board of Regents, and a New Faculty Development Award of the University of South Dakota. MJM was supported by an NIH grant GM066287.

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Authors and Affiliations

  1. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, 57069, USA

    G. Dong, J. M. Ferguson, D. Zhang, K. Rezvani & H. Wang

  2. Department of Biology, University of South Dakota, Vermillion, SD, 57069, USA

    A. J. Duling & R. G. Nicholas

  3. Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, MD, 21201, USA

    S. Fang & M. J. Monteiro

  4. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA

    S. Li & X-J. Li

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  1. G. Dong
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  2. J. M. Ferguson
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  3. A. J. Duling
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  4. R. G. Nicholas
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  9. S. Li
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  11. H. Wang
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Correspondence to H. Wang.

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Dong, G., Ferguson, J.M., Duling, A.J. et al. Modeling Pathogenesis of Huntington’s Disease with Inducible Neuroprogenitor Cells. Cell Mol Neurobiol 31, 737–747 (2011). https://doi.org/10.1007/s10571-011-9679-0

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  • DOI: https://doi.org/10.1007/s10571-011-9679-0

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