Cocchi Enrico, Drago Antonio, Serretti Alessandro
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
IRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy.
Mol Neurobiol. 2016 Apr;53(3):2065-2081. doi: 10.1007/s12035-015-9174-6. Epub 2015 Apr 24.
Pruning in neurons has been suggested to be strongly involved in Schizophrenia's (SKZ) etiopathogenesis in recent biological, imaging, and genetic studies. We investigated the impact of protein-coding genes known to be involved in pruning, collected by a systematic literature research, in shaping the risk for SKZ in a case-control sample of 9,490 subjects (Psychiatric Genomics Consortium). Moreover, their modifications through evolution (humans, chimpanzees, and rats) and subcellular localization (as indicative of their biological function) were also investigated. We also performed a biological pathways (Gene Ontology) analysis. Genetics analyses found four genes (DLG1, NOS1, THBS4, and FADS1) and 17 pathways strongly involved in pruning and SKZ in previous literature findings to be significantly associated with the sample under analysis. The analysis of the subcellular localization found that secreted genes, and so regulatory ones, are the least conserved through evolution and also the most associated with SKZ. Their cell line and regional brain expression analysis found that their areas of primary expression are neuropil and the hippocampus, respectively. At the best of our knowledge, for the first time, we were able to describe the SKZ neurodevelopmental hypothesis starting from a single biological process. We can also hypothesize how alterations in pruning fine regulation and orchestration, strongly related with the evolutionary newest (and so more sensitive) secreted proteins, may be of particular relevance in the hippocampus. This early alteration may lead to a mis-structuration of neural connectivity, resulting in the different brain alteration that characterizes SKZ patients.
近期的生物学、影像学和遗传学研究表明，神经元修剪在精神分裂症的病因发病机制中起着重要作用。我们通过系统的文献研究收集了已知参与修剪的蛋白质编码基因，研究了它们在9490名受试者（精神疾病基因组学联盟）的病例对照样本中对精神分裂症风险形成的影响。此外，还研究了这些基因在进化过程（人类、黑猩猩和大鼠）中的修饰以及亚细胞定位（以指示其生物学功能）。我们还进行了生物途径（基因本体论）分析。遗传学分析发现，先前文献中发现的四个基因（DLG1、NOS1、THBS4和FADS1）和17条与修剪和精神分裂症密切相关的途径与所分析的样本显著相关。亚细胞定位分析发现，分泌基因以及调控基因在进化过程中保守性最低，且与精神分裂症的关联性最强。对其细胞系和脑区表达分析发现，它们的主要表达区域分别是神经毡和海马体。据我们所知，我们首次能够从单一生物过程出发描述精神分裂症的神经发育假说。我们还可以推测，与进化上最新的（因而更敏感的）分泌蛋白密切相关的修剪精细调节和编排的改变，在海马体中可能具有特别重要的意义。这种早期改变可能导致神经连接的结构紊乱，从而导致精神分裂症患者特有的不同脑部改变。
