RNAi of arcRNA hsrω affects sub-cellular localization of Drosophila FUS to drive neurodiseases

Abstract

Defective RNA metabolism is common pathogenic mechanisms involved in neurological disorders. Indeed, a conspicuous feature of some neurodegenerative diseases is the loss of nuclear activities of RNA-binding proteins (RBPs) like Fused in sarcoma (FUS) and eventually, their accumulation in cytoplasmic proteinaceous inclusions. Long non-coding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes, including neurological disorders. A subset of these lncRNAs is the core of nuclear bodies (NBs), which are the sites of RNA processing and sequestration of specific ribonucleoproteins (RNPs) complexes. In Drosophila melanogaster the lncRNA hsrω is the architectural RNA (arcRNA) of the NB omega speckles (ω-speckles). Here, we show that the neuron-specific and motor neuron-specific knockdown of hsrω impairs locomotion in larval and adult flies and induces anatomical defects in presynaptic terminals of motor neurons, suggesting a novel role of arcRNA hsrω in development of neuromuscular junctions. Since RBPs are recognized as important regulators of neuronal activities, to examine the molecular mechanism of such neurodegeneration, we analysed interaction between hsrω and Drosophila orthologue of human FUS (dFUS). Strictly, we found that dFUS genetically and physically interacts with the arcRNA hsrω. Moreover, we revealed that a fine regulation of gene expression occurs between hsrω and dFUS and surprisingly, we uncover that depletion of hsrω affects the sub-cellular compartmentalization of dFUS thus, enhancing its cytoplasmic localization and inducing its loss of nuclear function. The model we propose shows the role of arcRNA in diseases affecting the nervous system and in particular it elucidates the molecular mechanism underlying the loss of dFUS nuclear function in the absence of its mutations. Our new findings could provide new insights into the pathogenesis of neurodegenerative disease dependent on mis-function or mis-localization of aggregation prone RNA binding proteins like FUS in Amyotrophic Lateral Sclerosis.