OBJECTIVE The mechanisms leading to schizophrenia are likely to be diverse. However, there may be common pathophysiological pathways for subtypes of the disease. The authors tested the hypothesis that increased protein insolubility and ubiquitination underlie the pathophysiology for a subtype of schizophrenia. METHODS Prefrontal cortex and superior temporal gyrus from postmortem brains of individuals with and without schizophrenia were subjected to cold sarkosyl fractionation, separating proteins into soluble and insoluble fractions. Protein insolubility and ubiquitin levels were quantified for each insoluble fraction, with normalization to total homogenate protein. Mass spectrometry analysis was then performed to identify the protein contents of the insoluble fractions. The potential biological relevance of the detected proteins was assessed using Gene Ontology enrichment analysis and Ingenuity Pathway Analysis. RESULTS A subset of the schizophrenia brains showed an increase in protein insolubility and ubiquitination in the insoluble fraction. Mass spectrometry of the insoluble fraction revealed that brains with increased insolubility and ubiquitination exhibited a similar peptide expression by principal component analysis. The proteins that were significantly altered in the insoluble fraction were enriched for pathways relating to axon target recognition as well as nervous system development and function. CONCLUSIONS This study suggests a pathological process related to protein insolubility for a subset of patients with schizophrenia. Determining the molecular mechanism of this subtype of schizophrenia could lead to a better understanding of the pathways underlying the clinical phenotype in some patients with major mental illness as well as to improved nosology and identification of novel therapeutic targets.

中文翻译：

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精神分裂症患者亚型增加了大脑中蛋白质的不溶性。

目的导致精神分裂症的机制可能是多种多样的。但是，对于该疾病的亚型，可能存在常见的病理生理途径。作者检验了以下假设，即蛋白质不溶性和泛素化增加是精神分裂症亚型病理生理的基础。方法对患有和不患有精神分裂症的人的死后大脑的前额叶皮层和颞上回进行冷sarkosyl分级分离，将蛋白质分为可溶和不可溶部分。定量每个不溶级分的蛋白不溶性和泛素水平，并标准化为总匀浆蛋白。然后进行质谱分析以鉴定不溶级分的蛋白质含量。使用基因本体论富集分析和独创性途径分析评估了检测到的蛋白质的潜在生物学相关性。结果精神分裂症大脑的一个子集显示蛋白质不溶性和不溶部分中的泛素化增加。不溶部分的质谱分析显示，通过主成分分析，具有增加的不溶性和泛素化的大脑表现出相似的肽表达。在不溶级分中发生显着变化的蛋白质富含与轴突靶标识别以及神经系统发育和功能有关的途径。结论这项研究提出了与一部分精神分裂症患者蛋白质不溶性相关的病理过程。