The endoplasmic reticulum-stress response is induced in several neurodegenerative diseases and in cellular models of Huntington's disease. However, here we report that the processing of ATF6α to its active nuclear form, one of the three branches of endoplasmic reticulum-stress activation, is impaired in both animal models and Huntington's disease patients. ATF6α has been reported to be essential for the survival of dormant tumour cells that, like neurons, are arrested in the G0–G1 phase of the cell cycle. This effect is mediated by the small GTPase Rheb (Ras-homologue enriched in brain). Our results suggest that the ATF6α/Rheb pathway is altered in Huntington's disease as the decrease in ATF6α processing is accompanied by a decrease in the accumulation of Rheb. These alterations correlate with the aberrant accumulation of cell cycle re-entry markers in post-mitotic neurons which is accompanied by death of a subset of neurons.