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. This evidence concerns the gene KEAP1 and amyotrophic lateral sclerosis.