Inhibition of cytosolic Phospholipase A2 prevents prion peptide-induced neuronal damage and co-localisation with Beta III Tubulin.
Inhibition of cytosolic Phospholipase A2 prevents prion peptide-induced neuronal damage and co-localisation with Beta III Tubulin.
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DOI：
10.1186/1471-2202-13-106
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发表时间：
2012-08-28
期刊：
影响因子：
2.4
通讯作者：
Werling D
中科院分区：
文献类型：
--
作者：
Last V;Williams A;Werling D
磷脂酶A2（PLA 2）的激活和花生四烯酸（AA）的代谢，以胡萝卜素已被证明在神经退行性疾病的神经元死亡中发挥重要作用。在这里，我们报告了朊病毒肽片段HuPrP 106 -126对原代皮层神经元中的PLA 2级联反应和cPLA 2向神经突的易位的影响。原代皮层神经元暴露于HuPrP 106 -126增加了磷酸化cPLA 2的水平，并导致磷酸化cPLA 2以PrP依赖的方式从细胞体重新定位到细胞神经突，这是以前未报道的观察结果。HuPrP 106 -126还诱导显著的AA释放，这是cPLA 2活化的指标;这在突触损伤和随后的细胞死亡之前。p-cPLA 2的新易位假定暴露于HuPrP 106 -126导致细胞骨架重排的可能性。然而，p-cPLA 2没有与F-肌动蛋白，中间丝，或微管相关蛋白共定位显着。相反，p-cPLA 2与细胞骨架蛋白β III微管蛋白显著共定位。用PLA 2抑制剂棕榈酰三氟甲基酮（PACOCF 3）预处理减少cPLA 2活化、AA释放和对神经元突触的损伤。此外，PACOCF 3减少了神经突中p-cPLA 2的表达，并抑制了与β III微管蛋白的共定位，从而防止了PrP诱导的细胞死亡。总的来说，这些发现表明cPLA 2在HuPrP 106 -126的作用中起着至关重要的作用，并且p-cPLA 2与β III微管蛋白的共定位可能是朊病毒肽引起的神经变性进展的中心。需要进一步的工作来确切地定义PLA 2抑制剂如何保护神经元免受肽诱导的毒性，以及这与神经变性中发生的细胞内结构变化如何相关。
Activation of phospholipase A2 (PLA2) and the subsequent metabolism of arachidonic acid (AA) to prostaglandins have been shown to play an important role in neuronal death in neurodegenerative disease. Here we report the effects of the prion peptide fragment HuPrP106-126 on the PLA2 cascade in primary cortical neurons and translocation of cPLA2 to neurites. Exposure of primary cortical neurons to HuPrP106-126 increased the levels of phosphorylated cPLA2 and caused phosphorylated cPLA2 to relocate from the cell body to the cellular neurite in a PrP-dependent manner, a previously unreported observation. HuPrP106-126 also induced significant AA release, an indicator of cPLA2 activation; this preceded synapse damage and subsequent cellular death. The novel translocation of p-cPLA2 postulated the potential for exposure to HuPrP106-126 to result in a re-arrangement of the cellular cytoskeleton. However p-cPLA2 did not colocalise significantly with F-actin, intermediate filaments, or microtubule-associated proteins. Conversely, p-cPLA2 did significantly colocalise with the cytoskeletal protein beta III tubulin. Pre-treatment with the PLA2 inhibitor, palmitoyl trifluoromethyl ketone (PACOCF3) reduced cPLA2 activation, AA release and damage to the neuronal synapse. Furthermore, PACOCF3 reduced expression of p-cPLA2 in neurites and inhibited colocalisation with beta III tubulin, resulting in protection against PrP-induced cell death. Collectively, these findings suggest that cPLA2 plays a vital role in the action of HuPrP106-126 and that the colocalisation of p-cPLA2 with beta III tubulin could be central to the progress of neurodegeneration caused by prion peptides. Further work is needed to define exactly how PLA2 inhibitors protect neurons from peptide-induced toxicity and how this relates to intracellular structural changes occurring in neurodegeneration.
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影响因子：
4.8
作者：
Bate, C;Reid, S;Williams, A
通讯作者：
Williams, A
影响因子：
3.5
作者：
Balsinde, J;Winstead, MV;Dennis, EA
通讯作者：
Dennis, EA
影响因子：
4.8
作者：
Gu, YP;Fujioka, H;Singh, N
通讯作者：
Singh, N
溴烯醇内酯和三氟甲基酮对巨噬细胞 CA2+-独立磷脂酶 A(2) 的抑制
影响因子：
4.8
作者：
ACKERMANN, EJ;CONDEFRIEBOES, K;DENNIS, EA
通讯作者：
DENNIS, EA
DOI：
10.1016/j.bbrc.2004.01.126
发表时间：
2004-03-19
影响因子：
3.1
作者：
Hachiya, NS;Watanabe, K;Kaneko, K
通讯作者：
Kaneko, K