Wasser Catherine R, Masiulis Irene, Durakoglugil Murat S, Lane-Donovan Courtney, Xian Xunde, Beffert Uwe, Agarwala Anandita, Hammer Robert E, Herz Joachim
Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Sci Signal. 2014 Nov 25;7(353):ra113. doi: 10.1126/scisignal.2005438.
Apoer2 is an essential receptor in the central nervous system that binds to the apolipoprotein ApoE. Various splice variants of Apoer2 are produced. We showed that Apoer2 lacking exon 16, which encodes the O-linked sugar (OLS) domain, altered the proteolytic processing and abundance of Apoer2 in cells and synapse number and function in mice. In cultured cells expressing this splice variant, extracellular cleavage of OLS-deficient Apoer2 was reduced, consequently preventing γ-secretase-dependent release of the intracellular domain of Apoer2. Mice expressing Apoer2 lacking the OLS domain had increased Apoer2 abundance in the brain, hippocampal spine density, and glutamate receptor abundance, but decreased synaptic efficacy. Mice expressing a form of Apoer2 lacking the OLS domain and containing an alternatively spliced cytoplasmic tail region that promotes glutamate receptor signaling showed enhanced hippocampal long-term potentiation (LTP), a phenomenon associated with learning and memory. However, these mice did not display enhanced spatial learning in the Morris water maze, and cued fear conditioning was reduced. Reducing the expression of the mutant Apoer2 allele so that the abundance of the protein was similar to that of Apoer2 in wild-type mice normalized spine density, hippocampal LTP, and cued fear learning. These findings demonstrated a role for ApoE receptors as regulators of synaptic glutamate receptor activity and established differential receptor glycosylation as a potential regulator of synaptic function and memory.
载脂蛋白E受体2（Apoer2）是中枢神经系统中的一种重要受体，可与载脂蛋白ApoE结合。Apoer2可产生多种剪接变体。我们发现，缺少编码O-连接糖（OLS）结构域的第16外显子的Apoer2，会改变细胞中Apoer2的蛋白水解过程和丰度，以及小鼠的突触数量和功能。在表达这种剪接变体的培养细胞中，缺乏OLS的Apoer2的细胞外切割减少，从而阻止了Apoer2细胞内结构域的γ-分泌酶依赖性释放。表达缺乏OLS结构域的Apoer2的小鼠，其大脑中Apoer2丰度增加、海马棘密度增加、谷氨酸受体丰度增加，但突触效能降低。表达一种缺乏OLS结构域且含有促进谷氨酸受体信号传导的可变剪接细胞质尾区的Apoer2形式的小鼠，表现出海马长时程增强（LTP）增强，这是一种与学习和记忆相关的现象。然而，这些小鼠在莫里斯水迷宫中并未表现出增强的空间学习能力，并减少了线索恐惧条件反射。降低突变型Apoer2等位基因的表达，使蛋白质丰度与野生型小鼠中的Apoer2相似，可使棘密度、海马LTP和线索恐惧学习正常化。这些发现证明了ApoE受体作为突触谷氨酸受体活性调节剂的作用，并确立了差异受体糖基化作为突触功能和记忆的潜在调节剂。
