1. Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence
- Author
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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, and Seth G.N. Grant
- Subjects
tandem affinity purification ,PSD95 ,Arc ,synaptic complexes ,supercomplexes ,genetic variants ,cognition ,intellectual disability ,schizophrenia ,Biology (General) ,QH301-705.5 - Abstract
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.
- Published
- 2017
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