A specific synaptic adaptor for NEDD4 E3 ubiquitin ligases is necessary for synaptic plasticity and motor learning

I. González-Calvo, K. Iyer, M. Carquin, A. Khayachi, F.A. Giuliani, J. Vincent, M. Séveno, S.M. Sigoillot, M. Veleanu, S. Tahraoui, M. Albert, O. Vigy, Y. Nadjar, A. Dumoulin, A. Triller, J.-L. Bessereau, L. Rondi-Reig, P. Isope, F. Selimi

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Received Date: 24th January 20

Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here we show that SUSD4, an uncharacterized complement-related transmembrane protein, tethers ubiquitin E3 ligases of the NEDD4 subfamily, allowing the formation of a complex with the AMPA receptor subunit GLUA2 and its activity-dependent degradation. SUSD4 is expressed by many neuronal populations starting at the time of synapse formation. Loss-of-function of Susd4 in the mouse prevents long-term depression at cerebellar synapses, and leads to impairment in motor coordination adaptation and learning. Our findings reveal that activity-dependent synaptic plasticity relies on the targeting of the degradation machinery to specific substrates through the use of a synaptic adaptor. This mechanism potentially accounts for the role of SUSD4 mutations in neurodevelopmental diseases. 

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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