CHANGES IN ACTIN DYNAMICS AND F-ACTIN STRUCTURE BOTH IN SYNAPTONEUROSOMES OF LRRK2(R1441G) MUTANT MICE AND IN PRIMARY HUMAN FIBROBLASTS OF LRRK2(G2019S) MUTATION CARRIERS
CHANGES IN ACTIN DYNAMICS AND F-ACTIN STRUCTURE BOTH IN SYNAPTONEUROSOMES OF LRRK2(R1441G) MUTANT MICE AND IN PRIMARY HUMAN FIBROBLASTS OF LRRK2(G2019S) MUTATION CARRIERS
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DOI：
10.1016/j.neuroscience.2014.09.070
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发表时间：
2015-01-22
期刊：
影响因子：
3.3
通讯作者：
Gillardon, F.
中科院分区：
文献类型：
--
作者：
Caesar, M.;Felk, S.;Gillardon, F.
越来越多的证据表明，帕金森病相关的富含亮氨酸重复序列激酶2（LRRK 2）通过调节肌动蛋白动力学来调节细胞功能。在本研究中，我们研究了LRRK 2在成年LRRK 2基因敲除和LRRK 2（R1441 G）转基因小鼠以及LRRK 2（G2019 S）突变携带者的原代成纤维细胞中的功能性突触末梢中的作用。我们发现，缺乏LRRK 2的减少和过度表达的突变LRRK 2的年龄依赖性增加的肌动蛋白解聚剂Latrunculin A（LatA）的突触细胞骨架的影响。类似地，内源性突变体LRRK 2增加了原代成纤维细胞对LatA的敏感性。然而，在基础条件下，这些成纤维细胞显示出F-肌动蛋白束的增加和丝状伪足长度的减少，这可以通过LatA处理来挽救。我们的数据表明，LRRK 2改变肌动蛋白动力学和F-肌动蛋白结构在大脑神经元和皮肤成纤维细胞。我们推测，增加F-肌动蛋白捆绑代表一种补偿机制，以保护F-肌动蛋白的解聚作用的突变体LRRK 2在基础条件下。我们的数据进一步表明，LRRK 2依赖的细胞骨架的变化可能有功能的后果突触后NMDA受体定位。(C)2014年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Converging evidence suggests that the Parkinson's disease-linked leucine-rich repeat kinase 2 (LRRK2) modulates cellular function by regulating actin dynamics. In the present study we investigate the role of LRRK2 in functional synaptic terminals of adult LRRK2-knockout and LRRK2(R1441G)-transgenic mice as well as in primary fibroblasts of LRRK2(G2019S) mutation carriers. We show that lack of LRRK2 decreases and overexpression of mutant LRRK2 age-dependently increases the effect of the actin depolymerizing agent Latrunculin A (LatA) on the synaptic cytoskeleton. Similarly, endogenous mutant LRRK2 increases sensitivity to LatA in primary fibroblasts. Under basal conditions however, these fibroblasts show an increase in F-actin bundles and a decrease in filopodial length which can be rescued by LatA treatment. Our data suggest that LRRK2 alters actin dynamics and F-actin structure both in brain neurons and skin fibroblasts. We hypothesize that increased F-actin bundling represents a compensatory mechanism to protect F-actin from the depolymerizing effect of mutant LRRK2 under basal conditions. Our data further indicate that LRRK2-dependent changes in the cytoskeleton might have functional consequences on postsynaptic NMDA receptor localization. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.