Increased Protein Insolubility in Brains From a Subset of Patients With Schizophrenia
Increased Protein Insolubility in Brains From a Subset of Patients With Schizophrenia
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DOI：
10.1176/appi.ajp.2019.18070864
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发表时间：
2019-09-01
影响因子：
17.7
通讯作者：
Nucifora, Frederick C., Jr.
中科院分区：
文献类型：
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作者：
Nucifora, Leslie G.;MacDonald, Matthew L.;Nucifora, Frederick C., Jr.
目的：导致精神分裂症的机制可能是多种多样的。然而，对于该疾病的亚型，可能存在共同的病理生理途径。作者测试了一种假设，即增加的蛋白质不溶性和泛素化是精神分裂症亚型病理生理学的基础。方法：对精神分裂症患者和非精神分裂症患者死后大脑的前额叶皮层和颞上回进行冷萨科齐分离，将蛋白质分离为可溶和不溶部分。蛋白不溶性和泛素水平对每个不溶性部分进行量化，并归一化到总均浆蛋白。然后进行质谱分析，以确定不溶性部分的蛋白质含量。利用基因本体富集分析和独创性途径分析评估检测到的蛋白质的潜在生物学相关性。结果：精神分裂症脑的一个子集显示出蛋白质不溶性和泛素化在不溶性部分的增加。质谱分析表明，不溶性和泛素化增加的大脑表现出类似的肽表达。在不溶性部分中显著改变的蛋白质在与轴突目标识别以及神经系统发育和功能相关的通路中富集。结论：本研究提示了一种与精神分裂症患者的蛋白质不溶性相关的病理过程。确定这种精神分裂症亚型的分子机制可以更好地理解一些重大精神疾病患者临床表型的潜在途径，并改进病分学和确定新的治疗靶点。
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.