Polyglutamine expansion disturbs the endoplasmic reticulum formation, leading to caspase-7 activation through Bax

•ER morphology is disrupted in a mouse model of Huntington’s disease (HD).•Caspase-7 activation induced by polyglutamine is triggered by insertion of Bax into the ER membrane.•The insertion of Bax into the ER membrane is induced by expression of a polyglutamine-containing protein. The endoplasmic reticulum (ER) plays a pivotal role in cellular functions such as the ER stress response. However, the effect of the ER membrane on caspase activation remains unclear. This study reveals that polyglutamine oligomers augmented at ER induce insertion of Bax into the ER membrane, thereby activating caspase-7. In line with the role of ER in cell death induced by polyglutamine expansion, the ER membrane was found to be disrupted and dilated in the brain of a murine model of Huntington’s disease. We can conclude that polyglutamine expansion may drive caspase-7 activation by disrupting the ER membrane.