Updated publication reference for PubMed record(s): 30209068. Several RNA-binding proteins (RBPs) are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including the FET proteins FUS, TAF15 and EWSR1. Cabeza (caz) is the single Drosophila FET ortholog. Here, we identified Xrp1, a poorly characterized DNA-binding protein, as a key modifier of caz mutant phenotypes. Xrp1 expression was strongly upregulated in caz mutants, and Xrp1 heterozygosity rescued their motor defects and life span. Interestingly, selective neuronal Xrp1 knock-down was sufficient to rescue, and neuronal Xrp1 overexpression phenocopied caz mutant phenotypes. The caz/Xrp1 genetic interaction depended on the functionality of the AT-hook DNA-binding domain in Xrp1. Consistently, caz mutants displayed gene expression dysregulation, which was mitigated by Xrp1 heterozygosity. Finally, Xrp1 knock-down substantially rescued the motor deficits and life span of flies expressing ALS-mutant FUS in motor neurons. Taken together, caz mutant phenotypes are mediated by increased neuronal Xrp1 levels, leading to gene expression dysregulation and neuronal dysfunction.