Mitochondrial-dependent Ca2+ handling in Huntington's disease striatal cells:: Effect of histone deacetylase inhibitors
Mitochondrial-dependent Ca2+ handling in Huntington's disease striatal cells:: Effect of histone deacetylase inhibitors
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DOI：
10.1523/jneurosci.3004-06.2006
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发表时间：
2006-10-25
影响因子：
5.3
通讯作者：
Rego, A. Cristina
中科院分区：
文献类型：
--
作者：
Oliveira, Jorge M. A.;Chen, Sylvia;Rego, A. Cristina
有证据表明，亨廷顿氏病（HD）纹状体的神经元功能障碍涉及线粒体功能和Ca2+处理的缺陷。然而，在完整的HD纹状体细胞中，线粒体和Ca2+处理之间的关系尚未完全研究。在HD模型中，用组蛋白去乙酰化酶（HDAC）抑制剂治疗可减少细胞死亡，但这种有希望的治疗方法对细胞功能的影响尚不清楚。在这里，我们使用细胞内Ca2+和线粒体膜电位的实时功能成像来探索原位HD线粒体在Ca2+处理中的作用。用表达全长突变亨廷顿蛋白（Htt）的转基因小鼠的永生化纹状体（STHdh）细胞和纹状体神经元来建立HD模型。我们发现(1)STHdh细胞中活跃的糖酵解会阻断线粒体在Ca2+处理中的作用以及线粒体抑制剂的作用，(2)没有糖酵解的STHdh细胞和纹状体神经元严重依赖于氧化磷酸化来处理能量依赖性的Ca2+。(3)全长突变体Htt的表达与线粒体依赖的Ca2+处理缺陷有关，可以通过HDAC抑制剂治疗来改善（用曲古斯汀A或丁酸钠治疗可以降低在Ca2+离子载体挑战后失去Ca2+稳态的STHdh细胞的比例，并加速NMDA挑战的纹状体神经元细胞内Ca2+的恢复）。(4)对NMDA受体激活具有不同反应模式的神经元表现出不同的平均体细胞区域，并且受到HDAC抑制剂治疗的不同影响，提示亚群或功能状态特异性。这些发现表明，HDAC抑制剂诱导的神经保护涉及更有效的Ca2+处理，从而提高神经元应对兴奋毒性刺激的能力。
Evidence suggests that neuronal dysfunction in Huntington's disease (HD) striatum involves deficits in mitochondrial function and in Ca2+ handling. However, the relationship between mitochondria and Ca2+ handling has been incompletely studied in intact HD striatal cells. Treatment with histone deacetylase (HDAC) inhibitors reduces cell death in HD models, but the effects of this promising therapy on cellular function are mostly unknown. Here, we use real-time functional imaging of intracellular Ca2+ and mitochondrial membrane potential to explore the role of in situ HD mitochondria in Ca2+ handling. Immortalized striatal (STHdh) cells and striatal neurons from transgenic mice, expressing full-length mutant huntingtin (Htt), were used to model HD. We show that (1) active glycolysis in STHdh cells occludes the mitochondrial role in Ca2+ handling as well as the effects of mitochondrial inhibitors, (2) STHdh cells and striatal neurons in the absence of glycolysis are critically dependent on oxidative phosphorylation for energy-dependent Ca2+ handling, (3) expression of full-length mutant Htt is associated with deficits in mitochondrial-dependent Ca2+ handling that can be ameliorated by treatment with HDAC inhibitors (treatment with trichostatin A or sodium butyrate decreases the proportion of STHdh cells losing Ca2+ homeostasis after Ca2+-ionophore challenging, and accelerates the restoration of intracellular Ca2+ in striatal neurons challenged with NMDA), and (4) neurons with different response patterns to NMDA receptor activation exhibit different average somatic areas and are differentially affected by treatment with HDAC inhibitors, suggesting subpopulation or functional state specificity. These findings indicate that neuroprotection induced by HDAC inhibitors involves more efficient Ca2+ handling, thus improving the neuronal ability to cope with excitotoxic stimuli.