Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling.
Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling.
复制标题
DOI：
10.1016/j.neurobiolaging.2011.06.017
复制
发表时间：
2011-12
影响因子：
4.2
通讯作者：
Robakis NK
中科院分区：
文献类型：
--
作者：
Xu J;Xilouri M;Bruban J;Shioi J;Shao Z;Papazoglou I;Vekrellis K;Robakis NK
为了减少毒性损伤（如谷氨酸兴奋性毒性和氧化应激）的损伤，神经元可能会部署一系列神经保护机制。最近的报道显示，导致失活蛋白的颗粒蛋白原（PGRN）基因无效或错义突变与额颞叶变性（FTLD）相关，表明某些神经元群体的存活需要功能性PGRN的完全表达。在这里，我们表明，细胞外PRGN刺激磷酸化/激活的神经元MEK/ERK/p90 RSK和PI 3 K/Akt细胞的生存途径和拯救皮层神经元从谷氨酸或氧化应激诱导的细胞死亡。MEK/ERK/p90 RSK信号传导的药理学抑制阻断PGRN诱导的磷酸化和针对谷氨酸毒性的神经保护，而MEK/ERK/p90 RSK或PI 3 K/Akt的抑制阻断PGRN针对神经毒素MPP+的保护。两种途径的抑制对PGRN依赖性神经保护对抗MPP+毒性具有协同作用，表明两种途径都有助于PGRN的神经保护活性。细胞外PGRN在神经元培养物中非常稳定，表明神经保护活性与全长蛋白质相关。总之，我们的数据表明，细胞外PRGN作为一种神经保护因子，并支持这一假设，即在FTLD中，功能性脑PGRN的减少导致存活信号减少，神经元对兴奋性毒性和氧化应激的保护减少，导致加速神经元细胞死亡。细胞外PGRN具有针对毒性损伤的神经保护功能，表明该蛋白质的体外制剂可用于治疗。
To reduce damage from toxic insults such as glutamate excitotoxicity and oxidative stresses, neurons may deploy an array of neuroprotective mechanisms. Recent reports show that progranulin (PGRN) gene null or missense mutations leading to inactive protein, are linked to frontotemporal lobar degeneration (FTLD), suggesting that survival of certain neuronal populations need full expression of functional PGRN. Here we show that extracellular PRGN stimulates phosphorylation/activation of the neuronal MEK/ERK/p90RSK and PI3K/Akt cell survival pathways and rescues cortical neurons from cell death induced by glutamate or oxidative stresses. Pharmacological inhibition of MEK/ERK/p90RSK signaling blocks the PGRN-induced phosphorylation and neuroprotection against glutamate toxicity whilst inhibition of either MEK/ERK/p90RSK or PI3K/Akt blocks PGRN protection against neurotoxin MPP+. Inhibition of both pathways had synergistic effects on PGRN-dependent neuroprotection against MPP+ toxicity suggesting both pathways contribute to the neuroprotective activities of PGRN. Extracellular PGRN is remarkably stable in neuronal cultures indicating neuroprotective activities are associated with full-length protein. Together, our data show that extracellular PRGN acts as a neuroprotective factor and support the hypothesis that in FTLD, reduction of functional brain PGRN results in reduced survival signaling and decreased neuronal protection against excitotoxicity and oxidative stress leading to accelerated neuronal cell death. That extracellular PGRN has neuroprotective functions against toxic insults suggests that in vitro preparations of this protein may be used therapeutically.
登录
查看更多内容
影响因子：
4
作者：
Bateman, Andrew;Bennett, Hugh P. J.
通讯作者：
Bennett, Hugh P. J.
影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
11.2
作者：
Monami, Giada;Gonzalez, Eva M.;Morrione, Andrea
通讯作者：
Morrione, Andrea
影响因子：
15.9
作者：
Kessenbrock, Kai;Froehlich, Leopold;Jenne, Dieter E.
通讯作者：
Jenne, Dieter E.
影响因子：
3
作者：
KOH, JY;CHOI, DW
通讯作者：
CHOI, DW