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Myelin Abnormalities in Schizophrenia: Insights from Proteomic Investigations of Post-Mortem Schizophrenia and Pre-Clinical Animal Models

机译:精神分裂症中的髓磷脂异常:从蛋白质组学研究的观点,该蛋白质组学研究是关于老年后精神分裂症和临床前动物模型的

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摘要

Accumulating evidence from epidemiologic and clinical findings report that both exposure to prenatal inflammation and prenatal iron deficiency significantly increase the risk of developing Schizophrenia in the offspring. Abnormalities in myelin are the most robust neuropathological findings in post-mortem human Schizophrenia, however the exact mechanisms at the protein and pathway levels owing to the myelin deficits are largely unknown.Animal models offer a fruitful approach to study the neurobiological basis of brain disturbances relevant to Schizophrenia. Furthermore, they are vital tools for testing hypotheses which cannot be directly assessed in human subjects for ethical and technical reasons. The advantage of animal models universally lies in the fact that they present a more accessible form o f a complex human phenomenon. Animal models of prenatal inflammation and prenatal iron deficiency converge on the evidence for abnormal myelin in Schizophrenia. Therefore, they represent advantageous avenues for myelin research, the discovery of novel myelin related mechanisms and putative drug targets.We hypothesised that myelin dysregulation would be present in post-mortem human Schizophrenia and in preclinical animal models of prenatal inflammation and prenatal iron deficiency. Using predominantly discovery-based proteomics, we aimed to reveal signalling pathways to explain the myelin deficits and provide more insight into the observed myelin pathology in Schizophrenia.Our data suggests a decrease in myelin specific, and myelin related proteins in the prefrontal cortex of adult rodent offspring prenatally exposed to inflammation or iron deficiency which could relate to the myelin abnormalities present in post-mortem human Schizophrenia. A collective dysregulation was also observed in core metabolic and mitochondrial signalling, aspects of the mitogen activated protein kinase pathway, and evidence for oxidative stress. In the white matter of the dorsolateral prefrontal cortex of post-mortem human Schizophrenia we reported pathways affected by differential protein expression to include transport, signal transduction, energy pathways relating to sugar, lipid and carbohydrate metabolism, cell growth and maintenance. Additionally, upon enriching for the myelin proteome in the dorsolateral prefrontal cortex white matter we found significant changes in core myelin specific proteins accompanied by changes in protein signalling and protein trafficking pathways.Considering Schizophrenia unfolds during the late period of brain maturation while myelination is still continuing, such as adolescence, we also determined protein expression in the prefrontal cortex of adult rodents following exposure to adolescent Risperidone to shed light on biological mechanisms pertaining to antipsychotic treatment which may also lie at the heart of Schizophrenia myelin neuropathology. Our data suggest that Risperidone treatment in adolescence following exposure to prenatal inflammation or prenatal iron deficiency could prevent myelin and metabolic/mitochondrial related protein changes implicating a positive role of early intervention treatment to prevent these changes.The presented data contribute to the composition of a scenario that may lead to a better understanding of Schizophrenia pathogenesis. The collection of protein alterations identified here reinforces the importance of myelin in Schizophrenia, and reveals a number of new potential markers that may contribute to the understanding of the pathogenesis of this complex disease.
机译:流行病学和临床发现的越来越多的证据表明,暴露于产前炎症和产前铁缺乏都会显着增加后代患精神分裂症的风险。髓磷脂异常是死后人类精神分裂症中最强有力的神经病理学发现,但是,由于髓磷脂缺乏,在蛋白质和途径水平上的确切机制尚不清楚。动物模型为研究与脑部疾病相关的神经生物学基础提供了有效的方法。精神分裂症。此外,它们是检验假设的重要工具,这些假设由于道德和技术原因无法在人类受试者中直接评估。通常,动物模型的优点在于,它们代表了复杂的人类现象的更易访问的形式。产前炎症和产前铁缺乏的动物模型集中于精神分裂症中髓鞘异常的证据。因此,它们代表了髓磷脂研究的有利途径,新的髓磷脂相关机制的发现和推定的药物靶标。我们假设死后人类精神分裂症以及产前炎症和产前铁缺乏的临床前动物模型中将存在髓磷脂失调。我们主要使用基于发现的蛋白质组学,旨在揭示解释髓鞘缺陷的信号传导途径,并为观察到的精神分裂症中的髓磷脂病理学提供更多见识。产后暴露于炎症或铁缺乏症的后代可能与死后人类精神分裂症中存在的髓磷脂异常有关。在核心代谢和线粒体信号,有丝分裂原活化的蛋白激酶途径的各个方面以及氧化应激的证据中也观察到集体失调。在死后人类精神分裂症的背外侧前额叶皮层的白质中,我们报道了受差异蛋白质表达影响的途径,包括运输,信号转导,与糖,脂质和碳水化合物代谢有关的能量途径,细胞生长和维持。此外,在丰富了背外侧前额叶皮层白质中的髓磷脂蛋白质组后,我们发现核心髓磷脂特异性蛋白质发生了显着变化,并伴随着蛋白质信号传导和蛋白质运输途径的变化。例如青春期,我们还确定了成年啮齿类动物暴露于成年利培酮后在成年啮齿动物前额叶皮层中的蛋白质表达,从而阐明了与抗精神病药物治疗有关的生物学机制,这也可能是精神分裂症髓鞘神经病理学的核心。我们的数据表明,利培酮在青春期暴露于产前炎症或产前缺铁后可以预防髓磷脂和代谢/线粒体相关蛋白的变化,暗示了早期干预治疗对预防这些变化的积极作用。可能会导致对精神分裂症发病机理的更好理解。这里鉴定出的蛋白质改变的集合增强了髓磷脂在精神分裂症中的重要性,并揭示了许多新的潜在标志物,这些标志物可能有助于了解这种复杂疾病的发病机理。

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    Farrelly Lorna;

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