The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Neurobiol Dis. 2019 Apr;124:479-488. doi: 10.1016/j.nbd.2018.12.011. Epub 2018 Dec 24.
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.
遗传和分子研究表明，溴结构域包含 1 （BRD1）基因参与精神分裂症和双相情感障碍的发病机制。相应地，Brd1 靶向缺失杂合子的小鼠（Brd1 小鼠）表现出具有广泛转化相关性的行为表型，与精神疾病有关。BRD1 编码一种支架蛋白，通过调节组蛋白乙酰化来影响许多基因的表达。BRD1 靶基因已在细胞系中鉴定；然而，降低 Brd1 水平对大脑蛋白质组的影响在很大程度上是未知的。在这项研究中，我们应用基于标签的定量质谱法来描绘雌性 Brd1 小鼠的前额叶皮层、海马体和纹状体蛋白质组和突触体蛋白质组。我们成功地定量了 1537 到 2196 种蛋白质，并显示出蛋白质丰度和区室化的广泛变化。通过对人类遗传数据的综合分析，我们发现前额叶皮层和海马体中差异丰富的蛋白质富含精神分裂症风险，进一步将 BRD1 的作用与精神疾病联系起来。受影响的蛋白质进一步富集了与已知影响神经元和树突棘形态的过程相关的蛋白质，例如细胞骨架动力学和线粒体功能的调节。受这些发现的直接启发，我们研究了前扣带皮层锥体神经元的树突棘形态，发现它们发生了显著改变，包括小树突棘的尺寸减小和成熟蘑菇型的数量减少。总之，我们的研究描述了与 BRD1 功能障碍及其在精神疾病中的作用相关的已知和新机制，并为 Brd1 小鼠中改变的神经信号和认知的分子和细胞功能障碍提供了证据。
