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Arc requires PSD95 for assembly into postsynaptic complexes involved with brain disease and intelligence

Research output: Contribution to journalArticle

  • Esperanza Fernandez
  • Mark O. Collins
  • René A.W. Frank
  • F. Zhu
  • Maksym V. Kopanitsa
  • Jess Nithianantharajah
  • David G. Fricker
  • Kathryn A. Elsegood
  • Mike D R Croning
  • Giulia Cencelli
  • Claudia Bagni
  • Menachem Fromer
  • Shaun M Purcell
  • Andrew J. Pocklington
  • Jyoti S. Choudhary

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http://www.cell.com/cell-reports/abstract/S2211-1247(17)31335-9
Original languageEnglish
Pages (from-to)679-691
JournalCell Reports
Volume21
Issue number3
Early online date17 Oct 2017
DOIs
Publication statusPublished - 17 Oct 2017

Abstract

Arc is an activity regulated neuronal protein yet little is known about its protein interactions, assembly into multiprotein complexes, role in human disease and cognition. We applied an integrated proteomic and genetic strategy using targeted tagging of a Tandem Affinity Purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice, biochemical and proteomic characterization of native complexes in wild type and knockout mice, and human genetic analyses of disease and intelligence. TAP tagging enabled efficient purification of complexes and identification of many novel 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 Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism and epilepsy mutations and normal variants in intelligence. Arc-PSD95 postsynaptic complexes are targets for genetic variants impacting on human cognitive function.

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