Lurcher GRID2-induced death and depolarization can be dissociated in cerebellar Purkinje cells
Lurcher GRID2-induced death and depolarization can be dissociated in cerebellar Purkinje cells
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DOI：
10.1016/s0896-6273(03)00093-x
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发表时间：
2003-03-06
期刊：
影响因子：
16.2
通讯作者：
Mariani, J
中科院分区：
文献类型：
--
作者：
Selimi, F;Lohof, AM;Mariani, J
勒彻突变将GRID2受体转变为结构性开放的通道。在Lurcher杂合子小鼠中，小脑浦肯野细胞永久去极化，这一特征被认为是它们死亡的主要原因，从出生后第二周开始。更戏剧性的Lurcher纯合子表型被认为是由于突变等位基因的简单基因剂量效应。我们分析了只含有一份Lurcher等位基因的Lurcher/HotFoot异等位基因突变体的表型，没有野生型GRID2。我们的结果表明，在这些异等位基因突变体中缺乏野生型GRID2受体会导致早期大量的浦肯野细胞死亡，这与自噬的早期迹象相关。这种神经元死亡与去极化无关，可以通过最近发现的由GRID2、n-PIST和Beclin1形成的信号通路由Lurcher GRID2受体直接激活自噬来解释。
The Lurcher mutation transforms the GRID2 receptor into a constitutively opened channel. In Lurcher heterozygous mice, cerebellar Purkinje cells are permanently depolarized, a characteristic that has been thought to be the primary cause of their death, which occurs from the second postnatal week onward. The more dramatic phenotype of Lurcher homozygotes is thought to be due to a simple gene dosage effect of the mutant allele. We have analyzed the phenotype of Lurcher/hotfoot heteroallelic mutants bearing only one copy of the Lurcher allele and no wild-type Grid2. Our results show that the absence of wild-type GRID2 receptors in these heteroallelic mutants induces an early and massive Purkinje cell death that is correlated with early signs of autophagy. This neuronal death is independent of depolarization and can be explained by the direct activation of autophagy by Lurcher GRID2 receptors through the recently discovered signaling pathway formed by GRID2, n-PIST, and Beclin1.