Increasing progranulin levels and blockade of the ERK1/2 pathway: Upstream and downstream strategies for the treatment of progranulin deficient frontotemporal dementia
Increasing progranulin levels and blockade of the ERK1/2 pathway: Upstream and downstream strategies for the treatment of progranulin deficient frontotemporal dementia
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DOI：
10.1016/j.euroneuro.2014.12.007
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发表时间：
2015-03-01
影响因子：
5.6
通讯作者：
Martin-Requero, Angeles
中科院分区：
文献类型：
--
作者：
Alquezar, Carolina;Esteras, Noemi;Martin-Requero, Angeles
额颞叶退行性变性（FTLD）是一种神经退行性疾病，其特征是轻度发病和行为、社会认知和语言的进行性改变。功能缺失的前颗粒蛋白基因（GRN）突变是TDP-43蛋白内含物（FTLD- tdp）的主要原因。FTLD-TDP的疾病改善治疗尚不可用。越来越多的证据表明，细胞周期功能障碍可能在包括FTLD在内的神经退行性疾病中起致病作用。由于正核神经元的细胞周期重新进入似乎先于神经元死亡，因此假设旨在阻止细胞周期进展的策略将具有神经保护作用。我们实验室最近的研究发现，携带无GRN突变的FTLD-TDP患者的淋巴母细胞和PGRN缺陷的SH-SY5Y神经母细胞瘤细胞的细胞周期改变涉及ERK1/2信号通路的过度激活。在这项工作中，我们研究了PGRN增强药物和ERK1/2抑制剂在PGRN缺陷FTLD的细胞模型中的作用。我们在这里报道，通过亚酰苯胺羟肟酸（SAHA）或氯喹（CQ）恢复PGRN含量，通过阻断selumetinib （AZD6244）或MEK162 （ry -162）激活ERK1/2，使CDK6/pRb途径和PGRN缺陷细胞的增殖活性正常化。此外，我们发现SAHA和selumetinib可以阻止pgrn缺陷淋巴细胞的胞质TDP-43积累。考虑到这些药物能够穿过血脑屏障，并且假设在FTLD患者的淋巴细胞中观察到的细胞周期和信号的改变可能是该疾病的外周体征，我们的研究结果表明，这些治疗方法可能作为与GRN突变相关的FTLD的新型治疗药物。(C) 2015 Elsevier B.V.和ECNP。版权所有。
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder marked by mild-life onset and progressive changes in behavior, social cognition, and language. Loss-of-function progranulin gene (GRN) mutations are the major cause of FTLD with TDP-43 protein inclusions (FTLD-TDP). Disease-modifying treatments for FTLD-TDP are not available yet. Mounting evidence indicates that cell cycle dysfunction may play a pathogenic role in neurodegenerative disorders including FTLD. Since cell cycle re-entry of posmitotic neurons seems to precede neuronal death, it was hypothesized that strategies aimed at preventing cell cycle progression would have neuroprotective effects. Recent research in our laboratory revealed cell cycle alterations in lymphoblasts from FTLD-TDP patients carrying a null GRN mutation, and in PGRN deficient SH-SY5Y neuroblastoma cells, involving overactivation of the ERK1/2 signaling pathway. In this work, we have investigated the effects of PGRN enhancers drugs and ERK1/2 inhibitors, in these cellular models of PGRN-deficient FTLD. We report here that both restoring the PGRN content, by suberoylanilide hydroxamic acid (SAHA) or chloroquine (CQ), as blocking ERK1/2 activation by selumetinib (AZD6244) or MEK162 (ARRY-162), normalized the CDK6/pRb pathway and the proliferative activity of PGRN deficient cells. Moreover, we found that SAHA and selumetinib prevented the cytosolic TDP-43 accumulation in PGRN-deficient lymphoblasts. Considering that these drugs are able to cross the blood-brain barrier, and assuming that the alterations in cell cycle and signaling observed in lymphoblasts from FTLD patients could be peripheral signs of the disease, our results suggest that these treatments may serve as novel therapeutic drugs for FTLD associated to GRN mutations. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.