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.

Fernandez, E., Collins, M.o., Frank, R., Zhu, F., Kopanitsa, M.v., Nithianantharajah, J., et al. (2017). Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence. CELL REPORTS, 21(3), 679-691 [10.1016/j.celrep.2017.09.045].

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

Bagni C.
Membro del Collaboration Group
;
2017

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/13
English
Arc; PSD95; cognition; genetic variants; intellectual disability; schizophrenia; supercomplexes; synaptic complexes; tandem affinity purification; Animals; Cytoskeletal Proteins; Disks Large Homolog 4 Protein; Gene Knock-In Techniques; Humans; Mice, Knockout; Nerve Tissue Proteins; Nervous System; Proteomics; Synapses; Intelligence
Fernandez, E., Collins, M.o., Frank, R., Zhu, F., Kopanitsa, M.v., Nithianantharajah, J., et al. (2017). Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence. CELL REPORTS, 21(3), 679-691 [10.1016/j.celrep.2017.09.045].
Fernandez, E; Collins, Mo; Frank, Raw; Zhu, F; Kopanitsa, Mv; Nithianantharajah, J; Lempriere, Sa; Fricker, D; Elsegood, Ka; Mclaughlin, Cl; Croning, Mdr; Mclean, C; Armstrong, Jd; Hill, Wd; Deary, Ij; Cencelli, G; Bagni, C; Fromer, M; Purcell, Sm; Pocklington, Aj; Choudhary, Js; Komiyama, Nh; Grant, Sgn
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/239427
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