一种连接δ2谷氨酸受体与自噬的新型蛋白质复合物：对蹒跚小鼠神经退行性变的影响

A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice.

作者信息

Yue Zhenyu, Horton Antony, Bravin Monica, DeJager Philip L, Selimi Fekrije, Heintz Nathaniel

机构信息

Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

出版信息

Neuron. 2002 Aug 29;35(5):921-33. doi: 10.1016/s0896-6273(02)00861-9.

DOI:10.1016/s0896-6273(02)00861-9

PMID:12372286

Abstract

Autophagy is a pathway for bulk degradation of subcellular constituents that is hyperactivated in many neurodegenerative conditions. It has been considered a second form of programmed cell death. Death of cerebellar Purkinje cells in lurcher animals is due to a mutation in GluRdelta2 that results in its constitutive activation. Here we have identified protein interactions between GluRdelta2, a novel isoform of a PDZ domain-containing protein (nPIST) that binds to this receptor, and Beclin1. nPIST and Beclin1 can synergize to induce autophagy. GluRdelta2(Lc), but not GluRdelta2(wt), can also induce autophagy. Furthermore, dying lurcher Purkinje cells contain morphological hallmarks of autophagic death in vivo. These results provide strong evidence that a direct link exists between GluRdelta2(Lc) receptor and stimulation of the autophagic pathway in dying lurcher Purkinje cells.

摘要

自噬是一种亚细胞成分大量降解的途径，在许多神经退行性疾病中被过度激活。它被认为是程序性细胞死亡的第二种形式。蹒跚动物小脑浦肯野细胞的死亡是由于GluRdelta2突变导致其组成性激活。在这里，我们确定了GluRdelta2、一种与该受体结合的含PDZ结构域蛋白的新型异构体（nPIST）和Beclin1之间的蛋白质相互作用。nPIST和Beclin1可以协同诱导自噬。GluRdelta2（Lc）而非GluRdelta2（wt）也能诱导自噬。此外，垂死的蹒跚动物浦肯野细胞在体内含有自噬性死亡的形态学特征。这些结果提供了强有力的证据，表明GluRdelta2（Lc）受体与垂死的蹒跚动物浦肯野细胞中自噬途径的刺激之间存在直接联系。