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Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice

Sonu Sahadevan, Katharina M. Hembach, Elena Tantardini, Manuela Pérez-Berlanga, Marian Hruska-Plochan, Julien Weber, Petra Schwarz, Luc Dupuis, Mark D. Robinson, Pierre De Rossi, Magdalini Polymenidou
doi: https://doi.org/10.1101/2020.06.10.136010
Sonu Sahadevan
1Department of Quantitative Biomedicine, University of Zurich
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Katharina M. Hembach
1Department of Quantitative Biomedicine, University of Zurich
2Department of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zurich
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Elena Tantardini
1Department of Quantitative Biomedicine, University of Zurich
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Manuela Pérez-Berlanga
1Department of Quantitative Biomedicine, University of Zurich
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Marian Hruska-Plochan
1Department of Quantitative Biomedicine, University of Zurich
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Julien Weber
1Department of Quantitative Biomedicine, University of Zurich
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Petra Schwarz
3Institute of Neuropathology, University Hospital Zurich
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Luc Dupuis
4Inserm, University of Strasbourg
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Mark D. Robinson
2Department of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zurich
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Pierre De Rossi
1Department of Quantitative Biomedicine, University of Zurich
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Magdalini Polymenidou
1Department of Quantitative Biomedicine, University of Zurich
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  • For correspondence: magdalini.polymenidou@uzh.ch
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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.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 10, 2020.
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Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice
Sonu Sahadevan, Katharina M. Hembach, Elena Tantardini, Manuela Pérez-Berlanga, Marian Hruska-Plochan, Julien Weber, Petra Schwarz, Luc Dupuis, Mark D. Robinson, Pierre De Rossi, Magdalini Polymenidou
bioRxiv 2020.06.10.136010; doi: https://doi.org/10.1101/2020.06.10.136010
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Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice
Sonu Sahadevan, Katharina M. Hembach, Elena Tantardini, Manuela Pérez-Berlanga, Marian Hruska-Plochan, Julien Weber, Petra Schwarz, Luc Dupuis, Mark D. Robinson, Pierre De Rossi, Magdalini Polymenidou
bioRxiv 2020.06.10.136010; doi: https://doi.org/10.1101/2020.06.10.136010

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