A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death
A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by AlsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death
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DOI：
10.1074/jbc.m410508200
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发表时间：
2005-02-11
影响因子：
4.8
通讯作者：
Matsuoka, M
中科院分区：
文献类型：
--
作者：
Kanekura, K;Hashimoto, Y;Matsuoka, M
ALS 2基因的产物AlsinLF通过其Rho鸟嘌呤核苷酸交换因子结构域抑制Cu/Zn超氧化物歧化酶（SOD 1）诱导的神经毒性。我们在这里确定Rac 1，一个Rho家族的小GTdR，作为AlsinLF的Rho鸟嘌呤核苷酸交换因子活性的靶点。Rac 1与alsinLF有关联。Rac 1的GTP形式的量通过alsinLF的强制过表达而上调。我们进一步发现，不仅组成型活性Rac 1抑制运动神经元细胞死亡的SOD 1突变体，但alsinLF的神经保护活性被完全抑制敲低内源性Rac 1的表达与小干扰RNA的Rac 1，表明Rac 1是alsinLF介导的神经保护的主要效应。这种alsinLF/Rac 1介导的神经保护作用特异性地针对SOD 1突变体诱导的细胞死亡而发生，但不针对运动神经元NSC 34细胞中任何其他神经毒性损伤诱导的细胞死亡。我们进一步证明了alsinLF/Rac 1介导的神经保护信号被传递到磷脂酰肌醇3-激酶/Akt抗凋亡轴。在Akt家族的三种蛋白中，Akt 3是alsinLF/Rac 1介导的神经保护的主要下游介质，其对SOD 1 music诱导的神经毒性特别有效。
AlsinLF, the product of the ALS2 gene, inhibits Cu/Zn-superoxide dismutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overexpression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.