Delayed Cell Cycle Progression in STHdhQ111/HdhQ111 Cells, a Cell Model for Huntington’s Disease Mediated by microRNA-19a, microRNA-146a and microRNA-432

Several indirect evidences are available to indicate that abnormalities in cell cycle may contribute to pathogenesis of Huntington’s disease (HD). Here, we show that the cell cycle progression in STsdhQ111/HdhQ111cells, a cell model of HD, is delayed in S and G2-M phases compared to control STHdhQ7/HdhQ7cells. Expression of 17 genes, like PCNA and CHEK1, was increased in STHdhQ111/HdhQ111cells. Increased expressions of PCNA, CHEK1 and CCNA2, and an enhanced phosphorylation of Rb1 were observed in primary cortical neurons expressing mutant N-terminal huntingtin (HTT), R6/2 mice and STHdhQ111/HdhQ111 cells. This increase in the expressions of PCNA, CHEK1 and CCNA2 was found to be the result of decreased expressions of miR-432, miR-146a, and (miR-19a and miR-146a), respectively. Enhanced apoptosis was observed at late S phase and G2-M phase in STHdhQ111/HdhQ111cells. Exogenous expressions of these miRNAs in STHdhQ111/HdhQ111 cells rescued the abnormalities in cell cycle and apoptosis. We also observed that inhibitors of cell cycle could decrease cell death in a cell model of HD. Based on these results obtained in cell and animal model of HD, we propose that inhibition of cell cycle either by miRNA expressions or by using inhibitors could be a potential approach for the treatment of HD.