Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.10.136010v1?rss=1 Authors: Sahadevan, S., Hembach, K. M., Tantardini, E., Perez-Berlanga, M., Hruska-Plochan, M., Weber, J., Schwarz, P., Dupuis, L., Robinson, M. D., De Rossi, P., Polymenidou, M. Abstract: FUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages, accompanied by alterations in density and size of GABAergic synapses. RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS accumulation at the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration. Copy rights belong to original authors. Visit the link for more info