Dopamine D2 receptor stimulation potentiates PolyQ-Huntingtin-induced mouse striatal neuron dysfunctions via Rho/ROCK-II activation.
Dopamine D2 receptor stimulation potentiates PolyQ-Huntingtin-induced mouse striatal neuron dysfunctions via Rho/ROCK-II activation.
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DOI：
10.1371/journal.pone.0008287
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发表时间：
2009-12-15
期刊：
影响因子：
3.7
通讯作者：
Bétuing S
中科院分区：
文献类型：
--
作者：
Deyts C;Galan-Rodriguez B;Martin E;Bouveyron N;Roze E;Charvin D;Caboche J;Bétuing S
亨廷顿氏病（Huntington's disease，HD）是一种与多聚谷氨酰胺（polyglutaminine，PGA）扩增相关的神经退行性疾病。尽管在大脑中广泛表达扩展的polyQ-亨廷顿蛋白（ExpHtt），但纹状体神经元对突变的易感性更高。一个公认的假说是多巴胺能输入参与这种脆弱性。我们先前表明，D2受体刺激增加聚集体形成和神经元死亡诱导ExpHtt在原代纹状体神经元的文化，和慢性D2拮抗剂治疗保护纹状体功能障碍诱导ExpHtt在慢病毒诱导的模型系统在体内。目前的工作旨在阐明下游D2受体（D2 R）刺激与纹状体对ExpHtt的易感性有关的信号通路。使用原代纹状体神经元培养，转染标记的GFP版本的人外显子1 ExpHtt，和siRNA对D2 R或D1 R，我们证实，DA增强神经元功能障碍，通过D2 R，而不是D1 R的刺激。我们证明，D2激动剂治疗诱导Htt和ExpHtt表达神经元的神经炎性回缩和生长锥塌陷。然后，我们测试了Rho/ROCK信号通路的可能参与，这在细胞骨架的动态中起着关键作用，在这些过程中。ROCK的药理学抑制剂（Y27632和Hydroxyfasudil）以及针对ROCK-II的siRNA逆转了D2对神经炎回缩和生长锥塌陷的相关作用。我们显示D2受体刺激和Rho激活之间的耦合，以及Cofilin的过度磷酸化，ROCK-II通路的下游效应。重要的是，D2激动剂介导的ExpHtt诱导的聚集体形成和神经元死亡的增强作用被Y27632和羟基法舒地尔和ROCK-II siRNA完全逆转。我们的数据首次证明，D2 R诱导的HD脆弱性与Rho/ROCK信号通路的激活密切相关。包含Rho/ROCK抑制剂可能是一种有趣的治疗选择，旨在预防疾病的发作。
Huntington's disease (HD) is a polyglutamine-expanded related neurodegenerative disease. Despite the ubiquitous expression of expanded, polyQ-Huntingtin (ExpHtt) in the brain, striatal neurons present a higher susceptibility to the mutation. A commonly admitted hypothesis is that Dopaminergic inputs participate to this vulnerability. We previously showed that D2 receptor stimulation increased aggregate formation and neuronal death induced by ExpHtt in primary striatal neurons in culture, and chronic D2 antagonist treatment protects striatal dysfunctions induced by ExpHtt in a lentiviral-induced model system in vivo. The present work was designed to elucidate the signalling pathways involved, downstream D2 receptor (D2R) stimulation, in striatal vulnerability to ExpHtt. Using primary striatal neurons in culture, transfected with a tagged-GFP version of human exon 1 ExpHtt, and siRNAs against D2R or D1R, we confirm that DA potentiates neuronal dysfunctions via D2R but not D1R stimulation. We demonstrate that D2 agonist treatment induces neuritic retraction and growth cone collapse in Htt- and ExpHtt expressing neurons. We then tested a possible involvement of the Rho/ROCK signalling pathway, which plays a key role in the dynamic of the cytoskeleton, in these processes. The pharmacological inhibitors of ROCK (Y27632 and Hydroxyfasudil), as well as siRNAs against ROCK-II, reversed D2-related effects on neuritic retraction and growth cone collapse. We show a coupling between D2 receptor stimulation and Rho activation, as well as hyperphosphorylation of Cofilin, a downstream effector of ROCK-II pathway. Importantly, D2 agonist-mediated potentiation of aggregate formation and neuronal death induced by ExpHtt, was totally reversed by Y27632 and Hydroxyfasudil and ROCK-II siRNAs. Our data provide the first demonstration that D2R-induced vulnerability in HD is critically linked to the activation of the Rho/ROCK signalling pathway. The inclusion of Rho/ROCK inhibitors could be an interesting therapeutic option aimed at forestalling the onset of the disease.
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影响因子：
11.2
作者：
ALBIN, RL;REINER, A;YOUNG, AB
通讯作者：
YOUNG, AB
影响因子：
4.8
作者：
Amano, M;Ito, M;Kaibuchi, K
通讯作者：
Kaibuchi, K
DOI：
10.1073/pnas.0502698102
发表时间：
2005-08-23
影响因子：
11.1
作者：
Charvin, D;Vanhoutte, P;Caboche, J
通讯作者：
Caboche, J
影响因子：
6.1
作者：
Charvin, Delphine;Roze, Emmanuel;Caboche, Jocelyne
通讯作者：
Caboche, Jocelyne
影响因子：
56.9
作者：
GRAVELAND, GA;WILLIAMS, RS;DIFIGLIA, M
通讯作者：
DIFIGLIA, M