<i>Xrp1</i> genetically interacts with the ALS-associated <i>FUS</i> orthologue <i>caz</i> and mediates its toxicity

Abstract

<i>Cabeza</i> (<i>caz</i>) is the single <i>Drosophila melanogaster</i> orthologue of the human FET proteins FUS, TAF15, and EWSR1, which have been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we identified <i>Xrp1</i>, a nuclear chromatin-binding protein, as a key modifier of <i>caz</i> mutant phenotypes. Xrp1 expression was strongly up-regulated in <i>caz</i> mutants, and <i>Xrp1</i> heterozygosity rescued their motor defects and life span. Interestingly, selective neuronal Xrp1 knockdown was sufficient to rescue, and neuronal Xrp1 overexpression phenocopied <i>caz</i> mutant phenotypes. The <i>caz/Xrp1</i> genetic interaction depended on the functionality of the AT-hook DNA-binding domain in Xrp1, and the majority of Xrp1-interacting proteins are involved in gene expression regulation. Consistently, <i>caz</i> mutants displayed gene expression dysregulation, which was mitigated by <i>Xrp1</i> heterozygosity. Finally, <i>Xrp1</i> knockdown substantially rescued the motor deficits and life span of flies expressing ALS mutant FUS in motor neurons, implicating gene expression dysregulation in ALS-FUS pathogenesis.