Filipović Dragana, Novak Božidar, Xiao Jinqiu, Tadić Predrag, Turck Christoph W
Department of Molecular Biology and Endocrinology, "VINČA" Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia.
Proteomics and Biomarkers, Max Planck Institute for Psychiatry, 80804 Munich, Germany.
Int J Mol Sci. 2024 Mar 6;25(5):3026. doi: 10.3390/ijms25053026.
Chronic social isolation (CSIS) generates two stress-related phenotypes: resilience and susceptibility. However, the molecular mechanisms underlying CSIS resilience remain unclear. We identified altered proteome components and biochemical pathways and processes in the prefrontal cortex cytosolic fraction in CSIS-resilient rats compared to CSIS-susceptible and control rats using liquid chromatography coupled with tandem mass spectrometry followed by label-free quantification and STRING bioinformatics. A sucrose preference test was performed to distinguish rat phenotypes. Potential predictive proteins discriminating between the CSIS-resilient and CSIS-susceptible groups were identified using machine learning (ML) algorithms: support vector machine-based sequential feature selection and random forest-based feature importance scores. Predominantly, decreased levels of some glycolytic enzymes, G protein-coupled receptor proteins, the Ras subfamily of GTPases proteins, and antioxidant proteins were found in the CSIS-resilient vs. CSIS-susceptible groups. Altered levels of Gapdh, microtubular, cytoskeletal, and calcium-binding proteins were identified between the two phenotypes. Increased levels of proteins involved in GABA synthesis, the proteasome system, nitrogen metabolism, and chaperone-mediated protein folding were identified. Predictive proteins make CSIS-resilient vs. CSIS-susceptible groups linearly separable, whereby a 100% validation accuracy was achieved by ML models. The overall ratio of significantly up- and downregulated cytosolic proteins suggests adaptive cellular alterations as part of the stress-coping process specific for the CSIS-resilient phenotype.
慢性社会隔离（CSIS）会产生两种与应激相关的表型：恢复力和易感性。然而，CSIS恢复力背后的分子机制仍不清楚。我们使用液相色谱与串联质谱联用，随后进行无标记定量和STRING生物信息学分析，鉴定了CSIS恢复力大鼠与CSIS易感性大鼠和对照大鼠相比，前额叶皮质胞质部分中蛋白质组成分、生化途径和过程的变化。进行了蔗糖偏好试验以区分大鼠表型。使用机器学习（ML）算法：基于支持向量机的序列特征选择和基于随机森林的特征重要性评分，鉴定了区分CSIS恢复力组和CSIS易感性组的潜在预测蛋白。主要发现，与CSIS易感性组相比，CSIS恢复力组中一些糖酵解酶、G蛋白偶联受体蛋白、GTPases蛋白的Ras亚家族和抗氧化蛋白的水平降低。在两种表型之间鉴定了甘油醛-3-磷酸脱氢酶（Gapdh）、微管、细胞骨架和钙结合蛋白水平的变化。还鉴定了参与γ-氨基丁酸（GABA）合成、蛋白酶体系统、氮代谢和伴侣介导的蛋白质折叠的蛋白质水平升高。预测蛋白使CSIS恢复力组与CSIS易感性组线性可分，由此ML模型实现了100%的验证准确率。显著上调和下调的胞质蛋白的总体比例表明，适应性细胞改变是CSIS恢复力表型特异性应激应对过程的一部分。
