Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence

Publication date: 17 October 2017
Source:Cell Reports, Volume 21, Issue 3
Author(s): Esperanza Fernández, Mark O. Collins, René A.W. Frank, Fei Zhu, Maksym V. Kopanitsa, Jess Nithianantharajah, Sarah A. Lemprière, David Fricker, Kathryn A. Elsegood, Catherine L. McLaughlin, Mike D.R. Croning, Colin Mclean, J. Douglas Armstrong, W. David Hill, Ian J. Deary, Giulia Cencelli, Claudia Bagni, Menachem Fromer, Shaun M. Purcell, Andrew J. Pocklington, Jyoti S. Choudhary, Noboru H. Komiyama, Seth G.N. Grant
Arc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant. PSD95 was essential for Arc assembly into 1.5-MDa complexes and activity-dependent recruitment to excitatory synapses. Integrating human genetic data with proteomic data showed that Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism, and epilepsy mutations and normal variants in intelligence. We propose that Arc-PSD95 postsynaptic complexes potentially affect human cognitive function.

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Teaser

Fernández et al. use genetics and proteomics to study the Arc protein in the mouse brain. PSD95 recruits Arc to the synapse and assembles it into signaling complexes with neurotransmitter receptors and other proteins. Arc-PSD95 supercomplexes contain genetic variants previously linked to epilepsy, schizophrenia, intellectual disability, and IQ.


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