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

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 (IncRNAs) are emerging as important regulators of tissue physiology and disease processes, including neurological disorders. A subset of these IncRNAs 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 IncRNA hsr omega is the architectural RNA (arcRNA) of the NB omega speckles (omega-speckles). Here, we show that the neuron-specific and motor neuron-specific knockdown of hsr omega impairs locomotion in larval and adult flies and induces anatomical defects in presynaptic terminals of motor neurons, suggesting a novel role of arcRNA hsr omega 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 hsr omega and Drosophila orthologue of human FUS (dFUS). Strictly, we found that dFUS genetically and physically interacts with the arcRNA hsr omega. Moreover, we revealed that a fine regulation of gene expression occurs between hsr omega and dFUS and surprisingly, we uncover that depletion of hsr omega 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. (C) 2017 Elsevier Inc. All rights reserved.