Departments of Pharmaceutical Sciences, School of Pharmacy, University of California-, Irvine, CA 92697, USA.
Department of Computer Science, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA 92697, USA; Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California-Irvine, CA 92697, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2021 Jul 13;109:110255. doi: 10.1016/j.pnpbp.2021.110255. Epub 2021 Jan 27.
Primary cilia function as cells' antennas to detect and transduce external stimuli and play crucial roles in cell signaling and communication. The vast majority of cilia genes that are causally linked with ciliopathies are also associated with neurological deficits, such as cognitive impairments. Yet, the roles of cilia dysfunctions in the pathogenesis of psychiatric disorders have not been studied. Our aim is to identify patterns of cilia gene dysregulation in the four major psychiatric disorders: schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BP), and major depressive disorder (MDD). For this purpose, we acquired differentially expressed genes (DEGs) from the largest and most recent publicly available databases. We found that 42%, 24%, 17%, and 15% of brain-expressed cilia genes were significantly differentially expressed in SCZ, ASD, BP, and MDD, respectively. Several genes exhibited cross-disorder overlap, suggesting that typical cilia signaling pathways' dysfunctions determine susceptibility to more than one psychiatric disorder or may partially underlie their pathophysiology. Our study revealed that genes encoding proteins of almost all sub-cilia structural and functional compartments were dysregulated in the four psychiatric disorders. Strikingly, the genes of 75% of cilia GPCRs and 50% of the transition zone proteins were differentially expressed in SCZ. The present study is the first to draw associations between cilia and major psychiatric disorders, and is the first step toward understanding the role that cilia components play in their pathophysiological processes, which may lead to novel therapeutic targets for these disorders.
原发性纤毛作为细胞的天线，用于检测和转导外部刺激，并在细胞信号转导和通讯中发挥关键作用。与纤毛病相关的绝大多数纤毛基因也与神经缺陷有关，如认知障碍。然而，纤毛功能障碍在精神疾病发病机制中的作用尚未得到研究。我们的目的是确定四大精神疾病（精神分裂症、自闭症谱系障碍、双相情感障碍和重度抑郁症）中纤毛基因失调的模式。为此，我们从最大和最新的公开可用数据库中获取差异表达基因（DEGs）。我们发现，42%、24%、17%和 15%的脑表达纤毛基因在精神分裂症、自闭症谱系障碍、双相情感障碍和重度抑郁症中分别显著差异表达。一些基因表现出跨疾病重叠，表明典型的纤毛信号通路功能障碍决定了对一种以上精神疾病的易感性，或者可能部分是其病理生理学的基础。我们的研究表明，在四大精神疾病中，编码几乎所有纤毛结构和功能区室蛋白的基因都失调。引人注目的是，75%的纤毛 GPCR 基因和 50%的过渡区蛋白基因在精神分裂症中差异表达。本研究首次将纤毛与主要精神疾病联系起来，也是理解纤毛成分在其病理生理过程中所起作用的第一步，这可能为这些疾病提供新的治疗靶点。
