Regulated proteolytic processing of Reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators.
Regulated proteolytic processing of Reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators.
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DOI：
10.1371/journal.pone.0047793
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Knuesel I
中科院分区：
文献类型：
--
作者：
Krstic D;Rodriguez M;Knuesel I
细胞外信号蛋白Reelin在发育过程中对神经元的正常迁移和皮质分层是必不可少的，它也在成年人的大脑中表达，在那里它调节突触功能。已有研究表明，在体外，Reelin的蛋白分解处理降低了其信号活性，促进了Reelin的聚集，并且蛋白分解处理在包括阿尔茨海默病(AD)在内的各种神经系统疾病中受到影响。然而，调节失调的Reelin裂解的病理生理学意义，以及所涉及的蛋白水解酶和它们的调节物都是未知的。在此，我们鉴定了丝氨酸蛋白酶、组织型纤溶酶原激活物(TPA)和两种基质金属蛋白酶ADAMTS-4和ADAMTS-5为Reelin裂解酶。此外，我们还评估了几种内源性蛋白水解酶抑制物，包括金属蛋白酶组织抑制物(TIMPs)、α-2-巨球蛋白、多蛇蛋白，以及基质金属蛋白酶9(MMP9)对Reelin切割的影响，并描述了它们在这一过程中的复杂相互作用。最后，我们可以证明在小鼠的海马区，Reelin蛋白水解酶的表达水平和定位与Reelin有很大的重叠。虽然这种模式在正常衰老过程中保持稳定，但在AD小鼠模型中，它们蛋白水平的变化与Reelin聚集的加速相吻合。
The extracellular signaling protein Reelin, indispensable for proper neuronal migration and cortical layering during development, is also expressed in the adult brain where it modulates synaptic functions. It has been shown that proteolytic processing of Reelin decreases its signaling activity and promotes Reelin aggregation in vitro, and that proteolytic processing is affected in various neurological disorders, including Alzheimer's disease (AD). However, neither the pathophysiological significance of dysregulated Reelin cleavage, nor the involved proteases and their modulators are known. Here we identified the serine protease tissue plasminogen activator (tPA) and two matrix metalloproteinases, ADAMTS-4 and ADAMTS-5, as Reelin cleaving enzymes. Moreover, we assessed the influence of several endogenous protease inhibitors, including tissue inhibitors of metalloproteinases (TIMPs), α-2-Macroglobulin, and multiple serpins, as well as matrix metalloproteinase 9 (MMP-9) on Reelin cleavage, and described their complex interplay in the regulation of this process. Finally, we could demonstrate that in the murine hippocampus, the expression levels and localization of Reelin proteases largely overlap with that of Reelin. While this pattern remained stable during normal aging, changes in their protein levels coincided with accelerated Reelin aggregation in a mouse model of AD.
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影响因子：
2.7
作者：
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