Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness
Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness
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DOI：
10.1038/s41380-018-0133-2
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发表时间：
2019-07-01
影响因子：
11
通讯作者：
Korth, Carsten
中科院分区：
文献类型：
--
作者：
Bradshaw, Nicholas J.;Korth, Carsten
慢性精神疾病（CMI），如精神分裂症或复发性情感障碍，是一种复杂的疾病，既有遗传因素，也有非遗传因素。在许多其他慢性脑部疾病中，包括阿尔茨海默病、帕金森病、肌萎缩性侧索硬化症和额颞叶痴呆症，这种疾病的零星病例比基因驱动的家族病例更常见。然而，这些病症的病理学特征在于存在异常蛋白质稳态、蛋白质稳态，导致患者脑中主要不是源自基因突变的错误折叠或聚集的蛋白质。虽然在CMI患者中尚未检测到可见的聚集蛋白质沉积，但我们提出在这些条件下存在更微妙的蛋白质错误组装，这与许多神经退行性疾病早期阶段发现的精神病表型形成连续体。这种蛋白质病不需要依赖于遗传变异。在一个类似的方式，以建立异常的神经递质稳态在CMI，异常稳态的蛋白质是一个功能的声明，只能部分地解释，但肯定是互补的，遗传方法。在这里，我们审查的证据异常proteostasis签名从死后的人的情况下，在体内动物的工作，并在体外分析的候选蛋白质错误组装在CMI。在这方面，目前最好表征的五种蛋白质是DISC 1、dysbindin-1、CRMP 1、TRIOBP-1和NPAS 3。这些具有固有非结构化结构域的蛋白质的错误组装由细胞外应激物触发，从而为CMI的非遗传原因提供了汇聚点。
Chronic mental illnesses (CMI), such as schizophrenia or recurrent affective disorders, are complex conditions with both genetic and non-genetic elements. In many other chronic brain conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia, sporadic instances of the disease are more common than gene-driven familial cases. Yet, the pathology of these conditions can be characterized by the presence of aberrant protein homeostasis, proteostasis, resulting in misfolded or aggregated proteins in the brains of patients that predominantly do not derive from genetic mutations. While visible deposits of aggregated protein have not yet been detected in CMI patients, we propose the existence of more subtle protein misassembly in these conditions, which form a continuum with the psychiatric phenotypes found in the early stages of many neurodegenerative conditions. Such proteinopathies need not rely on genetic variation. In a similar manner to the established aberrant neurotransmitter homeostasis in CMI, aberrant homeostasis of proteins is a functional statement that can only partially be explained by, but is certainly complementary to, genetic approaches. Here, we review evidence for aberrant proteostasis signatures from post mortem human cases, in vivo animal work, and in vitro analysis of candidate proteins misassembled in CMI. The five best-characterized proteins in this respect are currently DISC1, dysbindin-1, CRMP1, TRIOBP-1, and NPAS3. Misassembly of these proteins with inherently unstructured domains is triggered by extracellular stressors and thus provides a converging point for non-genetic causes of CMI.