It is unclear why endogenous Nrf2 activation is insufficient in neurodegeneration, but at least for amyotrophic lateral sclerosis and Huntington’s disease, the available evidence suggests endogenous Nrf2 signalling is impaired in these diseases at the molecular level, involving aberrant TDP-43 or huntingtin, respectively. The gene discussed is NFE2L2; the disease is Huntington disease.