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Arc requires PSD95 for assembly into postsynaptic complexes involved with neural dysfunction and intelligence

Fernández, Esperanza, Collins, Mark O., Frank, René A.W., Zhu, Fei, Kopanitsa, Maksym V., Nithianantharajah, Jess, Lemprière, Sarah A., Fricker, David, Elsegood, Kathryn A., McLaughlin, Catherine L., Croning, Mike D.R., Mclean, Colin, Armstrong, J. Douglas, Hill, W. David, Deary, Ian J., Cencelli, Giulia, Bagni, Claudia, Fromer, Menachem, Purcell, Shaun M., Pocklington, Andrew J. ORCID:, Choudhary, Jyoti S., Komiyama, Noboru H. and Grant, Seth G.N. 2017. Arc requires PSD95 for assembly into postsynaptic complexes involved with neural dysfunction and intelligence. Cell Reports 21 (3) , pp. 679-691. 10.1016/j.celrep.2017.09.045

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Creative Commons Attribution (CC BY 4.0)
Publisher: Elsevier
ISSN: 2211-1247
Date of First Compliant Deposit: 26 October 2017
Date of Acceptance: 13 September 2017
Last Modified: 06 May 2023 18:39

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