Proteolytic fragments of laminin promote excitotoxic neurodegeneration by up-regulation of the KA1 subunit of the kainate receptor.
Proteolytic fragments of laminin promote excitotoxic neurodegeneration by up-regulation of the KA1 subunit of the kainate receptor.
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DOI：
10.1083/jcb.200803107
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发表时间：
2008-12-29
期刊：
影响因子：
--
通讯作者：
Strickland S
中科院分区：
文献类型：
--
作者：
Chen ZL;Yu H;Yu WM;Pawlak R;Strickland S
细胞外基质（ECM）蛋白层粘连蛋白的降解有助于海马兴奋性毒性细胞死亡，但这种作用的机制尚不清楚。为了研究这一过程，我们破坏了海马中层粘连蛋白γ1 （lamγ1）的表达。lamγ - 1敲除（KO）小鼠与对照小鼠具有相似的kainate （KA）受体基础表达，但lamγ - 1 KO小鼠对KA诱导的神经元死亡具有抗性。注射KA后，对照组小鼠的KA1亚基水平升高，而lamγ - 1 KO小鼠的KA1亚基水平不变。KA后，组织纤溶酶原激活物(tPA) -KO小鼠的KA1水平也没有变化，表明KA注射后KA1上调需要tPA和层粘连蛋白。在lamγ -1或tPA KO小鼠海马中注入纤溶酶消化的层粘连蛋白-1可恢复KA1上调和ka诱导的神经元变性。在体外和体内用特异性抗KA1抗体干扰KA1功能可防止ka诱导的神经元死亡。这些结果表明神经退行性变的新途径涉及ECM蛋白水解和KA1 KA受体亚基上调。
Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown. To study this process, we disrupted laminin γ1 (lamγ1) expression in the hippocampus. Lamγ1 knockout (KO) and control mice had similar basal expression of kainate (KA) receptors, but the lamγ1 KO mice were resistant to KA-induced neuronal death. After KA injection, KA1 subunit levels increased in control mice but were unchanged in lamγ1 KO mice. KA1 levels in tissue plasminogen activator (tPA)–KO mice were also unchanged after KA, indicating that both tPA and laminin were necessary for KA1 up-regulation after KA injection. Infusion of plasmin-digested laminin-1 into the hippocampus of lamγ1 or tPA KO mice restored KA1 up-regulation and KA-induced neuronal degeneration. Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo. These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.
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