Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS

Sonu Sahadevan, Katharina M. Hembach, Elena Tantardini, Manuela Pérez-Berlanga, Marian Hruska-Plochan, Salim Megat, Julien Weber, Petra Schwarz, Luc Dupuis, Mark D. Robinson, Pierre Rossi and Magdalini Polymenidou ()
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Sonu Sahadevan: University of Zurich
Katharina M. Hembach: University of Zurich
Elena Tantardini: University of Zurich
Manuela Pérez-Berlanga: University of Zurich
Marian Hruska-Plochan: University of Zurich
Salim Megat: Inserm, University of Strasbourg
Julien Weber: University of Zurich
Petra Schwarz: University Hospital Zurich
Luc Dupuis: Inserm, University of Strasbourg
Mark D. Robinson: University of Zurich
Pierre Rossi: University of Zurich
Magdalini Polymenidou: University of Zurich

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Mutations disrupting the nuclear localization of the RNA-binding protein FUS characterize a subset of amyotrophic lateral sclerosis patients (ALS-FUS). FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Using super-resolution imaging we determined that the localization of FUS within synapses occurs predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosomes, we identified synaptic FUS RNA targets, encoding proteins associated with synapse organization and plasticity. Significant increase of synaptic FUS during early disease in a mouse model of ALS was accompanied by alterations in density and size of GABAergic synapses. mRNAs abnormally accumulated at the synapses of 6-month-old ALS-FUS mice were enriched for FUS targets and correlated with those depicting increased short-term mRNA stability via binding primarily on multiple exonic sites. Our study indicates that synaptic FUS accumulation in early disease leads to synaptic impairment, potentially representing an initial trigger of neurodegeneration.

Date: 2021
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DOI: 10.1038/s41467-021-23188-8

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