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

Esperanza Fernandez; Mark O. Collins; René A.W.  Frank; Fei Zhu; Maksym V.  Kopanitsa; Jess Nithianantharajah; Sarah A. Lempriere; David G. 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

doi:10.1016/j.celrep.2017.09.045

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

Esperanza Fernandez, Mark O. Collins, René A.W. Frank, Fei Zhu, Maksym V. Kopanitsa, Jess Nithianantharajah, Sarah A. Lempriere, David G. 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. PocklingtonJyoti S. Choudhary, Noboru H. Komiyama, Seth G. N. Grant

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Pages (from-to)	679-691
Number of pages	13
Journal	Cell Reports
Volume	21
Issue number	3
Early online date	17 Oct 2017
DOIs	https://doi.org/10.1016/j.celrep.2017.09.045
Publication status	Published - 17 Oct 2017

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Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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http://www.cell.com/cell-reports/abstract/S2211-1247(17)31335-9Licence: All Rights Reserved

The Disconnected Mind Phase 3
Cox, S. & Deary, I.
UK-based charities
1/04/16 → 31/03/23
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research
Testing the common cause hypothesis of cognitive ageing in the Lothian birth cohort 1921
Deary, I., Bates, T., Gow, A. & Starr, J.
UK central government bodies/local authorities, health and hospital authorities
1/06/07 → 31/05/09
Project: Research

Seth Grant
- seth.granted.acuk
- Deanery of Clinical Sciences - Personal Chair of Molecular Neuroscience
- Centre for Clinical Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active
Noboru Komiyama
- Deanery of Clinical Sciences - Senior Lecturer
- Centre for Clinical Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active

Cite this

Fernandez, E., Collins, M. O., Frank, R. A. W., Zhu, F., Kopanitsa, M. V., Nithianantharajah, J., Lempriere, S. A., Fricker, D. G., Elsegood, K. A., McLaughlin, C. L., Croning, M. D. R., Mclean, C., Armstrong, J. D., Hill, W. D., Deary, I. J., Cencelli, G., Bagni, C., Fromer, M., Purcell, S. M., ... Grant, S. G. N. (2017). Arc requires PSD95 for assembly into postsynaptic complexes involved with brain disease and intelligence. Cell Reports, 21(3), 679-691. https://doi.org/10.1016/j.celrep.2017.09.045

@article{77386742ea914d76beeb45197c7685cc,

title = "Arc requires PSD95 for assembly into postsynaptic complexes involved with brain disease and intelligence",

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.",

author = "Esperanza Fernandez and Collins, {Mark O.} and Frank, {Ren{\'e} A.W.} and Fei Zhu and Kopanitsa, {Maksym V.} and Jess Nithianantharajah and Lempriere, {Sarah A.} and Fricker, {David G.} and Elsegood, {Kathryn A.} and McLaughlin, {Catherine L.} and Croning, {Mike D R} and Colin Mclean and Armstrong, {J. Douglas} and Hill, {W. David} and Deary, {Ian J.} and Giulia Cencelli and Claudia Bagni and Menachem Fromer and Purcell, {Shaun M} and Pocklington, {Andrew J.} and Choudhary, {Jyoti S.} and Komiyama, {Noboru H.} and Grant, {Seth G. N.}",

year = "2017",

month = oct,

day = "17",

doi = "10.1016/j.celrep.2017.09.045",

language = "English",

volume = "21",

pages = "679--691",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

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Fernandez, E, Collins, MO, Frank, RAW, Zhu, F, Kopanitsa, MV, Nithianantharajah, J, Lempriere, SA, Fricker, DG, 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 2017, 'Arc requires PSD95 for assembly into postsynaptic complexes involved with brain disease and intelligence', Cell Reports, vol. 21, no. 3, pp. 679-691. https://doi.org/10.1016/j.celrep.2017.09.045

TY - JOUR

T1 - Arc requires PSD95 for assembly into postsynaptic complexes involved with brain disease and intelligence

AU - Fernandez, Esperanza

AU - Collins, Mark O.

AU - Frank, René A.W.

AU - Zhu, Fei

AU - Kopanitsa, Maksym V.

AU - Nithianantharajah, Jess

AU - Lempriere, Sarah A.

AU - Fricker, David G.

AU - Elsegood, Kathryn A.

AU - McLaughlin, Catherine L.

AU - Croning, Mike D R

AU - Mclean, Colin

AU - Armstrong, J. Douglas

AU - Hill, W. David

AU - Deary, Ian J.

AU - Cencelli, Giulia

AU - Bagni, Claudia

AU - Fromer, Menachem

AU - Purcell, Shaun M

AU - Pocklington, Andrew J.

AU - Choudhary, Jyoti S.

AU - Komiyama, Noboru H.

AU - Grant, Seth G. N.

PY - 2017/10/17

Y1 - 2017/10/17

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2017.09.045

DO - 10.1016/j.celrep.2017.09.045

M3 - Article

SN - 2211-1247

VL - 21

SP - 679

EP - 691

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

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

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Projects

The Disconnected Mind Phase 3

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Testing the common cause hypothesis of cognitive ageing in the Lothian birth cohort 1921

Profiles

Seth Grant

Noboru Komiyama

Cite this