Kohno Takao
Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University.
Yakugaku Zasshi. 2017;137(10):1233-1240. doi: 10.1248/yakushi.17-00127.
Reelin is a large secreted glycoprotein that regulates embryonic neuronal lamination and adult synaptic function. Secreted Reelin binds to lipoprotein receptors expressed on neurons. The Reelin-receptor interaction induces phosphorylation of an intracellular adaptor protein Dab1, which is required for normal embryonic brain development and adult brain functions. It has been suggested that Reelin hypofunction plays a role in the pathogenesis of several neuropsychiatric diseases, such as schizophrenia, autism, and Alzheimer's disease. Thus upregulation of Reelin activity may ameliorate the symptoms of neuropsychiatric diseases. However, the regulatory mechanism underlying the functions of Reelin is largely unknown and there are no good animal models of Reelin malfunction; thus, causal relations between Reelin and neuropsychiatric diseases remain unclear. Recently, our studies have shown that proteolytic cleavage of the Reelin protein regulates its activity. Herein, we will review recent findings about relations between Reelin and Alzheimer's disease, and the mechanism underlying the regulation of Reelin function by proteolytic cleavage. Also, we will discuss the prospect of treating neuropsychiatric diseases by upregulation of Reelin activity.
Reelin是一种大型分泌型糖蛋白，可调节胚胎神经元分层和成人突触功能。分泌的Reelin与神经元上表达的脂蛋白受体结合。Reelin-受体相互作用诱导细胞内衔接蛋白Dab1的磷酸化，这是正常胚胎脑发育和成人脑功能所必需的。有人提出，Reelin功能减退在几种神经精神疾病的发病机制中起作用，如精神分裂症、自闭症和阿尔茨海默病。因此，上调Reelin活性可能会改善神经精神疾病的症状。然而，Reelin功能的调节机制在很大程度上尚不清楚，并且没有良好的Reelin功能障碍动物模型；因此，Reelin与神经精神疾病之间的因果关系仍不清楚。最近，我们的研究表明，Reelin蛋白的蛋白水解切割调节其活性。在此，我们将综述关于Reelin与阿尔茨海默病之间关系的最新发现，以及蛋白水解切割调节Reelin功能的机制。此外，我们还将讨论通过上调Reelin活性治疗神经精神疾病的前景。
