In summary we show that certain ALS-FTLD associated missense mutations of SQSTM1/p62 (P348L and G351A) impair its ability to regulate Keap1-Nrf2 signalling, adding to the growing evidence that alterations in cellular defence responses against oxidative (and chemical) stress may be relevant for disease aetiology. The gene discussed is NFE2L2; the disease is amyotrophic lateral sclerosis.