, Volume 31, Issue 5, pp 737-747

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.