PT  - JOURNAL ARTICLE
AU  - Sahadevan, Sonu
AU  - Hembach, Katharina M.
AU  - Tantardini, Elena
AU  - Pérez-Berlanga, Manuela
AU  - Hruska-Plochan, Marian
AU  - Weber, Julien
AU  - Schwarz, Petra
AU  - Dupuis, Luc
AU  - Robinson, Mark D.
AU  - De Rossi, Pierre
AU  - Polymenidou, Magdalini
TI  - Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice
AID  - 10.1101/2020.06.10.136010
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.10.136010
4099  - http://biorxiv.org/content/early/2020/06/10/2020.06.10.136010.short
4100  - http://biorxiv.org/content/early/2020/06/10/2020.06.10.136010.full
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.