RT Journal Article SR Electronic T1 Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.06.10.136010 DO 10.1101/2020.06.10.136010 A1 Sonu Sahadevan A1 Katharina M. Hembach A1 Elena Tantardini A1 Manuela PĂ©rez-Berlanga A1 Marian Hruska-Plochan A1 Julien Weber A1 Petra Schwarz A1 Luc Dupuis A1 Mark D. Robinson A1 Pierre De Rossi A1 Magdalini Polymenidou YR 2020 UL http://biorxiv.org/content/early/2020/06/10/2020.06.10.136010.abstract AB 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.Competing Interest StatementThe authors have declared no competing interest.