Andrews Jessica L, Goodfellow Frederic J, Matosin Natalie, Snelling Mollie K, Newell Kelly A, Huang Xu-Feng, Fernandez-Enright Francesca
Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia; Schizophrenia Research Institute, Sydney, NSW 2010, Australia.
Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia.
J Psychiatr Res. 2017 Jul;90:31-39. doi: 10.1016/j.jpsychires.2017.01.009. Epub 2017 Jan 18.
Gene expression analyses in post-mortem schizophrenia brains suggest that a number of ubiquitin proteasome system (UPS) genes are associated with schizophrenia; however the status of UPS proteins in the schizophrenia brain is largely unknown. Ubiquitin related proteins are inherently involved in memory, neuronal survival and morphology, which are processes implicated in neurodevelopmental disorders such as schizophrenia. We examined levels of five UPS proteins (Protein Inhibitor of Activated STAT2 [PIAS2], F-Box and Leucine rich repeat protein 21 [FBXL21], Mouse Double Minute 2 homolog [MDM2], Ubiquitin Carboxyl-Terminal Hydrolase-L1 [UCHL1] and Ubiquitin Conjugating Enzyme E2D1 [UBE2D1]) involved in these neuronal processes, within the dorsolateral prefrontal cortex of post-mortem schizophrenia subjects and matched controls (n = 30/group), in addition to across neurodevelopmental time-points (juvenile, adolescent and adult stages of life), utilizing a well-established neurodevelopmental phencyclidine (PCP) animal model of schizophrenia. We observed significant reductions in PIAS2, FBXL21 and MDM2 in schizophrenia subjects compared to controls (p-values ranging from 0.002 to 0.004). In our developmental PCP model, MDM2 protein was significantly reduced in adult PCP-treated rats compared to controls (p = 0.034). Additionally, FBXL21 (p = 0.022) and UCHL1 (p = 0.022) were significantly decreased, whilst UBE2D1 was increased (p = 0.022), in juvenile phencyclidine-treated rats compared to controls. This is the first study reporting alterations of UPS proteins in post-mortem human schizophrenia subjects and in a neurodevelopmental model of schizophrenia. The findings from this study provide strong support for a role of these UPS proteins in the pathology and development of schizophrenia.
对精神分裂症患者死后大脑进行的基因表达分析表明，许多泛素蛋白酶体系统（UPS）基因与精神分裂症有关；然而，UPS蛋白在精神分裂症大脑中的状态在很大程度上尚不清楚。泛素相关蛋白本身就参与记忆、神经元存活和形态形成，而这些过程与诸如精神分裂症等神经发育障碍有关。我们检测了参与这些神经元过程的五种UPS蛋白（活化STAT2蛋白抑制剂[PIAS2]、F-Box和富含亮氨酸重复蛋白21[FBXL21]、小鼠双微体2同源物[MDM2]、泛素羧基末端水解酶-L1[UCHL1]和泛素结合酶E2D1[UBE2D1]）在死后精神分裂症患者和匹配对照组（每组n = 30）背外侧前额叶皮质中的水平，此外还检测了在神经发育的各个时间点（幼年、青少年和成年阶段）的水平，采用了成熟的精神分裂症神经发育苯环己哌啶（PCP）动物模型。我们观察到，与对照组相比，精神分裂症患者的PIAS2、FBXL21和MDM2显著降低（p值范围为0.002至0.004）。在我们的发育性PCP模型中，与对照组相比，成年PCP处理大鼠的MDM2蛋白显著降低（p = 0.034）。此外，与对照组相比，幼年苯环己哌啶处理大鼠的FBXL21（p = 0.022）和UCHL1（p = 0.022）显著降低，而UBE2D1则升高（p = 0.022）。这是第一项报告死后人类精神分裂症患者和精神分裂症神经发育模型中UPS蛋白改变的研究。这项研究的结果为这些UPS蛋白在精神分裂症的病理和发育中的作用提供了有力支持。
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