Original Research

Cellular and Molecular Neurobiology

, Volume 31, Issue 5, pp 737-747

Modeling Pathogenesis of Huntington’s Disease with Inducible Neuroprogenitor Cells

  • G. DongAffiliated withDivision of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota
  • , J. M. FergusonAffiliated withDivision of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota
  • , A. J. DulingAffiliated withDepartment of Biology, University of South Dakota
  • , R. G. NicholasAffiliated withDepartment of Biology, University of South Dakota
  • , D. ZhangAffiliated withDivision of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota
  • , K. RezvaniAffiliated withDivision of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota
  • , S. FangAffiliated withCenter for Biomedical Engineering and Technology, University of Maryland
  • , M. J. MonteiroAffiliated withCenter for Biomedical Engineering and Technology, University of Maryland
  • , S. LiAffiliated withDepartment of Human Genetics, Emory University School of Medicine
    • , X-J. LiAffiliated withDepartment of Human Genetics, Emory University School of Medicine
    • , H. WangAffiliated withDivision of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota Email author 

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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.

Keywords

Huntington’s disease Pathogenesis Huntingtin Polyglutamine Neuron Neuroprogenitor