Inhibiting geranylgeranylation increases neurite branching and differentially activates cofilin in cell bodies and growth cones.
Inhibiting geranylgeranylation increases neurite branching and differentially activates cofilin in cell bodies and growth cones.
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DOI：
10.1007/s12035-014-8653-5
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发表时间：
2014-08
影响因子：
5.1
通讯作者：
Hynds, DiAnna L.
中科院分区：
文献类型：
--
作者：
Samuel, Filsy;Reddy, Jairus;Kaimal, Radhika;Segovia, Vianey;Mo, Huanbiao;Hynds, DiAnna L.
甲羟戊酸途径的抑制剂，包括高度处方的他汀类药物，减少胆固醇和类异戊二烯的产生，如香叶基香叶基焦磷酸盐。Rho家族的小鸟嘌呤三磷酸酶（GTP酶）需要异戊二烯化，特别是香叶基香叶基化来活化。由于Rho GTP酶是肌动蛋白丝重排的主要调节剂，这些重排是过程延伸、神经突分支和突触可塑性所需的，因此他汀类药物可能影响认知或从神经系统损伤中恢复。在这里，我们评估了如何操纵香叶基香叶基化影响神经母细胞瘤生长锥中的神经突起始、伸长和分支。当存在胆固醇来源时，他汀类药物洛伐他汀（20 μM）处理使神经突起始测量值降低17.0%至19.0%，并使神经突分支增加4.03至9.54倍（不考虑外源性胆固醇）。仅在无胆固醇的培养条件下，用洛伐他汀治疗可增加神经突伸长。用洛伐他汀治疗可使生长锥肌动蛋白丝含量降低24.3%。在所有情况下，与异戊烯化前体香叶基香叶醇（10 μM）共同治疗可逆转洛伐他汀的作用。在先前的工作中，他汀类药物对生长的影响与调节肌动蛋白解聚因子cofilin有关。在我们的测定中，用洛伐他汀或香叶基香叶醇处理降低了全细胞裂解物中的cofilin磷酸化。然而，洛伐他汀增加了细胞体中的cofilin磷酸化，并降低了生长锥中的cofilin磷酸化，表明在特定细胞区域的差异调节。总之，我们解释这些数据表明，蛋白质geranylgeranylation可能调节生长锥肌动蛋白丝含量和随后的神经突生长，通过机制，也影响肌动蛋白成核和聚合。
Inhibitors of the mevalonate pathway, including the highly prescribed statins, reduce the production of cholesterol and isoprenoids such as geranylgeranyl pyrophosphates. The Rho family of small guanine triphosphatases (GTPases) requires isoprenylation, specifically geranylgeranylation, for activation. Because Rho GTPases are primary regulators of actin filament rearrangements required for process extension, neurite arborization and synaptic plasticity, statins may affect cognition or recovery from nervous system injury. Here, we assessed how manipulating geranylgeranylation affects neurite initiation, elongation and branching in neuroblastoma growth cones. Treatment with the statin, lovastatin (20 μM) decreased measures of neurite initiation by 17.0% to 19.0% when a source of cholesterol was present and increased neurite branching by 4.03 to 9.54 fold (regardless of exogenous cholesterol). Neurite elongation was increased by treatment with lovastatin only in cholesterol-free culture conditions. Treatment with lovastatin decreased growth cone actin filament content by up to 24.3%. In all cases, co-treatment with the prenylation precursor, geranylgeraniol (10 μM), reversed the effect of lovastatin. In prior work, statin effects on outgrowth were linked to modulating the actin depolymerizing factor, cofilin. In our assays, treatment with lovastatin or geranylgeraniol decreased cofilin phosphorylation in whole cell lysates. However, lovastatin increased cofilin phosphorylation in cell bodies and decreased it in growth cones, indicating differential regulation in specific cell regions. Together, we interpret these data to suggest that protein geranylgeranylation likely regulates growth cone actin filament content and subsequent neurite outgrowth through mechanisms that also affect actin nucleation and polymerization.
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影响因子：
5.1
作者：
Li, Ling;Zhang, Wei;Cheng, Shaowu;Cao, Dongfeng;Parent, Marc
通讯作者：
Parent, Marc
影响因子：
5.3
作者：
Dent, EW;Barnes, AM;Kalil, K
通讯作者：
Kalil, K
DOI：
10.1002/neu.20258
发表时间：
2006-07-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
Loudon, Robert R.;Silver, Lee D.;Gallo, Gianluca
通讯作者：
Gallo, Gianluca
影响因子：
3.2
作者：
Gungabissoon, RA;Bamburg, JR
通讯作者：
Bamburg, JR
影响因子：
5.3
作者：
Hsieh, SHK;Ferraro, GB;Fournier, AE
通讯作者：
Fournier, AE