Azzam Sausan, Schlatzer Daniela, Nethery David, Saleh Dania, Li Xiaolin, Akladious Afaf, Chance Mark R, Strohl Kingman P
Center for Proteomics and Bioinformatics, Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA.
Pulmonary Critical Care and Sleep Medicine, Case Western Reserve University, Cleveland, OH, USA.
Proteomics. 2017 Jul;17(13-14). doi: 10.1002/pmic.201600478. Epub 2017 Jun 26.
Narcolepsy is a disabling neurological disorder of sleepiness linked to the loss of neurons producing orexin neuropeptides in the hypothalamus. Two well-characterized phenotypic mouse models of narcolepsy, loss-of-function (orexin-knockout), and progressive loss of orexin (orexin/ataxin-3) exist. The open question is whether the proteomics signatures of the hypothalamus would be different between the two models. To address this gap, we utilized a label-free proteomics approach and conducted a hypothalamic proteome analysis by comparing each disease model to that of wild type. Following data processing and statistical analysis, 14 484 peptides mapping to 2282 nonredundant proteins were identified, of which 39 proteins showed significant differences in protein expression across groups. Altered proteins in both models showed commonalties in pathways for mitochondrial dysfunction and neuronal degeneration, as well as altered proteins related to inflammatory demyelination, insulin resistance, metabolic responses, and the dopaminergic and monoaminergic systems. Model-specific alterations in insulin degraded enzyme (IDE) and synaptosomal-associated protein-25 were unique to orexin-KO and orexin/ataxin-3, respectively. For both models, proteomics not only identified clinically suspected consequences of orexin loss on energy homeostasis and neurotransmitter systems, but also identified commonalities in inflammation and degeneration despite the entirely different genetic basis of the two mouse models.
发作性睡病是一种使人衰弱的神经系统嗜睡症，与下丘脑产生食欲素神经肽的神经元丧失有关。存在两种特征明确的发作性睡病表型小鼠模型，即功能丧失型（食欲素基因敲除）和食欲素进行性丧失型（食欲素/共济失调蛋白-3）。一个悬而未决的问题是，这两种模型下丘脑的蛋白质组学特征是否会有所不同。为了填补这一空白，我们采用了一种无标记蛋白质组学方法，通过将每种疾病模型与野生型模型进行比较，对下丘脑蛋白质组进行了分析。经过数据处理和统计分析，共鉴定出14484个肽段，对应2282个非冗余蛋白质，其中39种蛋白质在各组间的蛋白质表达上存在显著差异。两种模型中发生改变的蛋白质在线粒体功能障碍和神经元变性途径上表现出共性，同时与炎症性脱髓鞘、胰岛素抵抗、代谢反应以及多巴胺能和单胺能系统相关的蛋白质也发生了改变。胰岛素降解酶（IDE）和突触体相关蛋白-25的模型特异性改变分别是食欲素基因敲除模型和食欲素/共济失调蛋白-3模型所特有的。对于这两种模型，蛋白质组学不仅确定了食欲素丧失对能量稳态和神经递质系统的临床疑似后果，而且还确定了尽管两种小鼠模型的遗传基础完全不同，但在炎症和变性方面的共性。
