Brain proteome changes in female Brd1+/− mice unmask dendritic spine pathology and show enrichment for schizophrenia risk

Veerle Paternoster; Maria Svanborg; Anders Valdemar Edhager; Anto P Rajkumar; Esben Ahlburg Eickhardt; Jonatan Pallesen; Jakob Grove; Per Qvist; Tue Fryland; Gregers Wegener; Jens Randel Nyengaard; Ole Mors; Johan Palmfeldt; Anders Dupont Børglum; Jane Hvarregaard Christensen

doi:10.1016/j.nbd.2018.12.011

Brain proteome changes in female Brd1^+/− mice unmask dendritic spine pathology and show enrichment for schizophrenia risk

Veerle Paternoster, Maria Svanborg, Anders Valdemar Edhager, Anto P Rajkumar, Esben Ahlburg Eickhardt, Jonatan Pallesen, Jakob Grove, Per Qvist, Tue Fryland, Gregers Wegener, Jens Randel Nyengaard, Ole Mors, Johan Palmfeldt, Anders Dupont Børglum, Jane Hvarregaard Christensen

Old Age Psychiatry

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Abstract

Genetic and molecular studies have implicated the Bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1^+/-mice) show behavioral phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied label-based quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1+/- mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies and compartmentalization. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex and hippocampus are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1^+/- mice.

Original language	English
Journal	Neurobiology of Disease
Early online date	24 Dec 2018
DOIs	https://doi.org/10.1016/j.nbd.2018.12.011
Publication status	E-pub ahead of print - 24 Dec 2018

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10.1016/j.nbd.2018.12.011

Brain proteome changes in_PATERNOSTER_Accepted18December2018_GREEN AAM (CC BY-NC-ND)Accepted author manuscript, 1.17 MBLicence: CC BY-NC-ND

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Paternoster, V., Svanborg, M., Edhager, A. V., Rajkumar, A. P., Eickhardt, E. A., Pallesen, J., Grove, J., Qvist, P., Fryland, T., Wegener, G., Nyengaard, J. R., Mors, O., Palmfeldt, J., Børglum, A. D., & Christensen, J. H. (2018). Brain proteome changes in female Brd1^+/− mice unmask dendritic spine pathology and show enrichment for schizophrenia risk. Neurobiology of Disease. Advance online publication. https://doi.org/10.1016/j.nbd.2018.12.011

@article{a9e6a9c9281648e89418a42677a80a5b,

title = "Brain proteome changes in female Brd1+/− mice unmask dendritic spine pathology and show enrichment for schizophrenia risk",

abstract = "Genetic and molecular studies have implicated the Bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1+/- mice) show behavioral phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied label-based quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1+/- mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies and compartmentalization. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex and hippocampus are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1+/- mice.",

author = "Veerle Paternoster and Maria Svanborg and Edhager, {Anders Valdemar} and Rajkumar, {Anto P} and Eickhardt, {Esben Ahlburg} and Jonatan Pallesen and Jakob Grove and Per Qvist and Tue Fryland and Gregers Wegener and Nyengaard, {Jens Randel} and Ole Mors and Johan Palmfeldt and B{\o}rglum, {Anders Dupont} and Christensen, {Jane Hvarregaard}",

note = "Copyright {\textcopyright} 2018. Published by Elsevier Inc.",

year = "2018",

month = dec,

day = "24",

doi = "10.1016/j.nbd.2018.12.011",

language = "English",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Elsevier",

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Paternoster, V, Svanborg, M, Edhager, AV, Rajkumar, AP, Eickhardt, EA, Pallesen, J, Grove, J, Qvist, P, Fryland, T, Wegener, G, Nyengaard, JR, Mors, O, Palmfeldt, J, Børglum, AD & Christensen, JH 2018, 'Brain proteome changes in female Brd1^+/− mice unmask dendritic spine pathology and show enrichment for schizophrenia risk', Neurobiology of Disease. https://doi.org/10.1016/j.nbd.2018.12.011

TY - JOUR

T1 - Brain proteome changes in female Brd1+/− mice unmask dendritic spine pathology and show enrichment for schizophrenia risk

AU - Paternoster, Veerle

AU - Svanborg, Maria

AU - Edhager, Anders Valdemar

AU - Rajkumar, Anto P

AU - Eickhardt, Esben Ahlburg

AU - Pallesen, Jonatan

AU - Grove, Jakob

AU - Qvist, Per

AU - Fryland, Tue

AU - Wegener, Gregers

AU - Nyengaard, Jens Randel

AU - Mors, Ole

AU - Palmfeldt, Johan

AU - Børglum, Anders Dupont

AU - Christensen, Jane Hvarregaard

PY - 2018/12/24

Y1 - 2018/12/24

N2 - Genetic and molecular studies have implicated the Bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1+/- mice) show behavioral phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied label-based quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1+/- mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies and compartmentalization. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex and hippocampus are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1+/- mice.

AB - Genetic and molecular studies have implicated the Bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1+/- mice) show behavioral phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied label-based quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1+/- mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies and compartmentalization. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex and hippocampus are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1+/- mice.

U2 - 10.1016/j.nbd.2018.12.011

DO - 10.1016/j.nbd.2018.12.011

M3 - Article

C2 - 30590179

SN - 0969-9961

JO - Neurobiology of Disease

JF - Neurobiology of Disease

ER -

Brain proteome changes in female Brd1+/− mice unmask dendritic spine pathology and show enrichment for schizophrenia risk

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Brain proteome changes in female Brd1^+/− mice unmask dendritic spine pathology and show enrichment for schizophrenia risk