Kinase Inhibitor Screening Identifies Cyclin-Dependent Kinases and Glycogen Synthase Kinase 3 as Potential Modulators of TDP-43 Cytosolic Accumulation during Cell Stress.
Kinase Inhibitor Screening Identifies Cyclin-Dependent Kinases and Glycogen Synthase Kinase 3 as Potential Modulators of TDP-43 Cytosolic Accumulation during Cell Stress.
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DOI：
10.1371/journal.pone.0067433
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
White AR
中科院分区：
文献类型：
--
作者：
Moujalled D;James JL;Parker SJ;Lidgerwood GE;Duncan C;Meyerowitz J;Nonaka T;Hasegawa M;Kanninen KM;Grubman A;Liddell JR;Crouch PJ;White AR
TAR DNA结合蛋白43（TDP-43）的异常加工已被确定为肌萎缩侧索硬化（ALS）或额颞叶变性（FTLD）期间神经元变性的主要因素。目前还不清楚TDP-43的变化，包括核到胞质的易位和随后的积累，在这些疾病中是如何控制的。TDP-43是异质性核糖核蛋白（hnRNP）RNA结合蛋白家族的成员，已知与ALS和FTLD中的细胞溶质RNA应激颗粒蛋白相关。hnRNP的运输和积累受特定激酶的作用控制，包括促分裂原活化蛋白激酶（MAPK）途径的成员。然而，很少有人知道激酶途径如何控制TDP-43的运动和积累。在这项研究中，我们使用TDP-43阳性应激颗粒形成的体外模型来筛选激酶抑制剂对TDP-43积累的影响。我们发现，虽然许多激酶抑制剂，特别是MAPK途径的抑制剂调节TDP-43和整体应激颗粒标志物人抗原R（HuR），但多种抑制剂对TDP-43积累更具特异性，包括细胞周期蛋白依赖性激酶（CDK）和糖原合成酶激酶3（GSK 3）的抑制剂。这些抑制剂对TDP-43、hnRNP K和TIAR的影响密切相关，但对HuR积累的影响往往不同。这可能表明TDP-43、hnRNP K和TIAR之间存在潜在的相互作用。还发现CDK抑制剂逆转预先形成的TDP-43阳性应激颗粒，并且CDK和GSK 3抑制剂都消除了转染细胞中C-末端TDP-43（219-414）的积累。需要进一步的研究来确认所涉及的特定激酶，以及它们的作用是否是通过磷酸化TDP-43结合伴侣hnRNP K。这些知识为控制异常细胞质TDP-43积累的机制提供了有价值的见解，并可能预示着ALS和FTLD中基于激酶调节的治疗干预的新机会。
Abnormal processing of TAR DNA binding protein 43 (TDP-43) has been identified as a major factor in neuronal degeneration during amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD). It is unclear how changes to TDP-43, including nuclear to cytosolic translocation and subsequent accumulation, are controlled in these diseases. TDP-43 is a member of the heterogeneous ribonucleoprotein (hnRNP) RNA binding protein family and is known to associate with cytosolic RNA stress granule proteins in ALS and FTLD. hnRNP trafficking and accumulation is controlled by the action of specific kinases including members of the mitogen-activated protein kinase (MAPK) pathway. However, little is known about how kinase pathways control TDP-43 movement and accumulation. In this study, we used an in vitro model of TDP-43-positve stress granule formation to screen for the effect of kinase inhibitors on TDP-43 accumulation. We found that while a number of kinase inhibitors, particularly of the MAPK pathways modulated both TDP-43 and the global stress granule marker, human antigen R (HuR), multiple inhibitors were more specific to TDP-43 accumulation, including inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3 (GSK3). Close correlation was observed between effects of these inhibitors on TDP-43, hnRNP K and TIAR, but often with different effects on HuR accumulation. This may indicate a potential interaction between TDP-43, hnRNP K and TIAR. CDK inhibitors were also found to reverse pre-formed TDP-43-positive stress granules and both CDK and GSK3 inhibitors abrogated the accumulation of C-terminal TDP-43 (219–414) in transfected cells. Further studies are required to confirm the specific kinases involved and whether their action is through phosphorylation of the TDP-43 binding partner hnRNP K. This knowledge provides a valuable insight into the mechanisms controlling abnormal cytoplasmic TDP-43 accumulation and may herald new opportunities for kinase modulation-based therapeutic intervention in ALS and FTLD.
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影响因子：
16
作者：
Chuang, Li-Chiou;Teixeira, Leonardo K.;Wohlschlegel, James A.;Henze, Martha;Yates, John R.;Mendez, Juan;Reed, Steven I.
通讯作者：
Reed, Steven I.
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作者：
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作者：
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影响因子：
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作者：
Hooper C;Killick R;Lovestone S
通讯作者：
Lovestone S
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.