Unraveling a role for dopamine in Huntington's disease:: The dual role of reactive oxygen species and D2 receptor stimulation
Unraveling a role for dopamine in Huntington's disease:: The dual role of reactive oxygen species and D2 receptor stimulation
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DOI：
10.1073/pnas.0502698102
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发表时间：
2005-08-23
影响因子：
11.1
通讯作者：
Caboche, J
中科院分区：
文献类型：
--
作者：
Charvin, D;Vanhoutte, P;Caboche, J
亨廷顿病(HD)是一种遗传性神经退行性疾病，由亨廷顿蛋白N末端区域的异常多谷氨酰胺延伸引起。这种突变会导致蛋白质聚集和神经毒性。尽管亨廷顿蛋白在大脑和身体中广泛表达，但突变的亨廷顿蛋白会导致纹状体投射神经元的选择性退化。在本研究中，我们研究了多巴胺(DA)在这一优先易损性中的作用。利用瞬时表达突变亨廷顿蛋白GFP标记外显子1的纹状体神经元的原代培养，我们发现低剂量的DA(100 MU M)与突变的亨廷顿蛋白协同作用，激活促凋亡转录因子c-Jun.令人惊讶的是，DA还增加了突变的亨廷顿蛋白在所有细胞间隔中的聚集形成，包括神经突起、胞体和细胞核。抗坏血酸(ROS)清除剂抗坏血酸和选择性c-jun氨基末端激酶途径抑制剂SP-600125可逆转依赖DA的c-jun激活增强作用。相反，DA对聚集形成的影响可被选择性D2受体拮抗剂逆转，并被D2激动剂重现。同样，D2基因敲除小鼠的纹状体神经元没有显示DA对聚集形成的影响。阻断ROS的产生、JNK的激活或D2受体的刺激可显著逆转亨廷顿蛋白突变所致纹状体死亡的DA加重。ROS清除剂和D2拮抗剂联合应用可完全逆转DA对亨廷顿蛋白突变所致纹状体死亡的影响。因此，本研究结果为HID纹状体易损性的细胞机制提供了洞察力，并有力地支持了JNK激活和D2受体信号在这一过程中的双重作用。
Huntington's disease (HD), an inherited neurodegenerative disorder, results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation leads to protein aggregation and neurotoxicity. Despite its widespread expression in the brain and body, mutated huntingtin causes selective degeneration of striatal projection neurons. In the present study, we investigate the role of dopamine (DA) in this preferential vulnerability. Using primary cultures of striatal neurons transiently expressing GFP-tagged-exon 1 of mutated huntingtin, we show that low doses of DA (100 mu M) act synergistically with mutated huntingtin to activate the proapoptotic transcription factor c-Jun. Surprisingly, DA also increases aggregate formation of mutated huntingtin in all cellular compartments, including neurites, soma, and nuclei. DA-dependent potentiation of c-Jun activation was reversed by ascorbate, a reactive oxygen species (ROS) scavenger, and SP-600125, a selective inhibitor of the c-Jun N-terminal kinase (JNK) pathway. By contrast, DA effects on aggregate formation were reversed by a selective D2 receptor antagonist and reproduced by a D2 agonist. Similarly, striatal neurons from D2 knockout mice showed no effect of DA on aggregate formation. Blocking ROS production, JNK activation, or D2 receptor stimulation significantly reversed DA aggravation of mutated huntingtin-induced striatal death. The combined treatment with the ROS scavenger and D2 antagonist totally reversed DA's effects on mutated huntingtin-induced striatal death. Thus, the present results provide insights into the cellular mechanisms that govern striatal vulnerability in HID and strongly support a dual role of JNK activation and D2 receptor signaling in this process.