Psiquiatria Molecular, Institut de Recerca Sant Joan de Déu, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain.
Department of Genome Sciences, School of Medicine, University of Washington, 3720 15th Ave NE, Seattle, WA 98195, USA.
Int J Mol Sci. 2021 Sep 17;22(18):10076. doi: 10.3390/ijms221810076.
Despite the growing importance of the cerebellum as a region highly vulnerable to accumulating molecular errors in schizophrenia, limited information is available regarding altered molecular networks with potential therapeutic targets. To identify altered networks, we conducted one-shot liquid chromatography-tandem mass spectrometry in postmortem cerebellar cortex in schizophrenia and healthy individuals followed by bioinformatic analysis (PXD024937 identifier in ProteomeXchange repository). A total of 108 up-regulated proteins were enriched in stress-related proteins, half of which were also enriched in axonal cytoskeletal organization and vesicle-mediated transport. A total of 142 down-regulated proteins showed an enrichment in proteins involved in mitochondrial disease, most of which were also enriched in energy-related biological functions. Network analysis identified a mixed module of mainly axonal-related pathways for up-regulated proteins with a high number of interactions for stress-related proteins. Energy metabolism and neutrophil degranulation modules were found for down-regulated proteins. Further, two double-hit postnatal stress murine models based on maternal deprivation combined with social isolation or chronic restraint stress were used to investigate the most robust candidates of generated networks. CLASP1 from the axonal module in the model of maternal deprivation was combined with social isolation, while YWHAZ was not altered in either model. METTL7A from the degranulation pathway was reduced in both models and was identified as altered also in previous gene expression studies, while NDUFB9 from the energy network was reduced only in the model of maternal deprivation combined with social isolation. This work provides altered stress- and mitochondrial disease-related proteins involved in energy, immune and axonal networks in the cerebellum in schizophrenia as possible novel targets for therapeutic interventions and suggests that METTL7A is a possible relevant altered stress-related protein in this context.
尽管小脑作为一个极易累积精神分裂症分子错误的区域变得越来越重要，但关于改变的分子网络及其潜在治疗靶点的信息有限。为了确定改变的网络，我们对精神分裂症患者和健康个体死后小脑皮质进行了一次液相色谱-串联质谱分析，随后进行了生物信息学分析（在 ProteomeXchange 存储库中使用 PXD024937 标识符）。共有 108 个上调蛋白在应激相关蛋白中富集，其中一半也在轴突细胞骨架组织和囊泡介导的运输中富集。共有 142 个下调蛋白在涉及线粒体疾病的蛋白中富集，其中大多数也在与能量相关的生物功能中富集。网络分析确定了一个以上调蛋白为主的混合模块，这些蛋白主要与轴突相关通路有关，与应激相关蛋白的相互作用数量较多。下调蛋白中发现了能量代谢和嗜中性粒细胞脱粒模块。此外，还使用了两种基于母体剥夺结合社会隔离或慢性束缚应激的双重打击产后应激小鼠模型，以研究产生网络的最稳健候选物。在母体剥夺模型的轴突模块中，CLASP1 与社会隔离相结合，而 YWHAZ 在两种模型中均未改变。脱粒途径中的 METTL7A 在两种模型中均减少，并在先前的基因表达研究中被鉴定为改变，而能量网络中的 NDUFB9 仅在母体剥夺结合社会隔离的模型中减少。这项工作提供了与精神分裂症小脑的应激和线粒体疾病相关的改变的蛋白，这些蛋白涉及能量、免疫和轴突网络，可能成为治疗干预的新靶点，并表明 METTL7A 是该背景下可能相关的改变的应激相关蛋白。
