TAR DNA-binding protein 43 (TDP43) is implicated in amyotrophic lateral sclerosis (ALS) and in some cases of frontotemporal dementia (FTD). Here, in a fly model of ALS–FTD, TDP43 reduced the recruitment of chromodomain-helicase-DNA-binding protein 1 (Chd1), a chromatin remodelling protein, to neuroprotective stress genes, resulting in reduced gene expression. TDP43 interacted directly with CHD2 (the human orthologue of Chd1), which is found at a reduced level in the cortex of individuals with FTD. This suggests that enhancing chromatin dynamics at stress genes might mitigate the effects of TDP43 in these disorders.