Striatal modulation of cAMP-response-element-binding protein (CREB) after excitotoxic lesions:: implications with neuronal vulnerability in Huntington's disease
Striatal modulation of cAMP-response-element-binding protein (CREB) after excitotoxic lesions:: implications with neuronal vulnerability in Huntington's disease
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DOI：
10.1111/j.1460-9568.2005.04545.x
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发表时间：
2006-01-01
影响因子：
3.4
通讯作者：
Fusco, FR
中科院分区：
文献类型：
--
作者：
Giampà, C;DeMarch, Z;Fusco, FR
最近的证据表明，亨廷顿病 (HD) 中 cAMP 反应元件结合蛋白 (CREB) 和 CREB 结合蛋白 (CBP) 的活性降低 [Steffan et al. 2017]。 (2000) 程序。国家科学院。科学。美国，97，6763-6768；吉内斯等人。 (2003) 嗯。摩尔。基因，12，497-508；鲁奥等人。 (2004)生物化学。药理学，68，1157-1164；糖等。 (2004) J.Biol。化学, 279, 4988-4999]。这种下降被认为反映了在 HD 小鼠模型中观察到的能量代谢受损，其中观察到纹状体 cAMP 水平下降 [Gines 等人，2017]。 (2003) 嗯。摩尔。基因，12，497-508]。 CREB水平的增加也已被证明可以发挥神经保护功能[Lonze & Ginty (2002) Neuron, 35, 605-623;隆兹等人。 (2002) 神经元，34, 371-385]。我们的研究旨在探讨与喹啉酸损伤的 HD 模型相比，正常大鼠纹状体神经元亚群中 CREB 的分布。 25只Wistar大鼠右侧纹状体注射100 mM喹啉酸，分别在24小时、48小时、1周、2周和6周后处死。对侧纹状体用作对照。使用针对磷酸化 CREB 的抗体和每种不同神经元亚群标记物进行双标记免疫荧光。我们的结果表明，投射神经元、小白蛋白（PARV）和钙视网膜素（CALR）中间神经元中激活的CREB水平逐渐降低，而胆碱能和生长抑素中间神经元中的这种水平保持稳定。因此，我们推测胆碱能中间神经元在兴奋性毒性损伤后维持其 CREB 水平的能力是决定其在亨廷顿舞蹈病中的保护作用的因素之一。
Recent evidence has shown that the activity of cAMP responsive element-binding protein (CREB) and of CREB-binding protein (CBP) is decreased in Huntington's disease (HD) [Steffan et al. (2000) Proc. Natl Acad. Sci. USA, 97, 6763-6768; Gines et al. (2003) Hum. Mol. Genet., 12, 497-508; Rouaux et al. (2004) Biochem. Pharmacol., 68, 1157-1164; Sugars et al. (2004) J. Biol. Chem., 279, 4988-4999]. Such decrease is thought to reflect the impaired energy metabolism observed in a HD mouse model, where a decline in striatum cAMP levels has been observed [Gines et al. (2003) Hum. Mol. Genet., 12, 497-508]. Increased levels of CREB have also been demonstrated to exert neuroprotective functions [Lonze & Ginty (2002) Neuron, 35, 605-623; Lonze et al. (2002) Neuron, 34, 371-385]. Our study aimed to investigate the distribution of CREB in the neuronal subpopulations of the striatum in normal rats compared to the HD model of quinolinic acid lesion. Twenty-five Wistar rats were administered quinolinic acid 100 mM into the right striatum, and killed after 24 h, 48 h, 1 week, 2 weeks, and six weeks, respectively. The contralateral striata were used as controls. Dual-label immunofluorescence was employed using antibodies against phosphorylated CREB and each of the different neuronal subpopulations markers. Our results show that activated CREB levels decrease progressively in projection neurons and parvalbumin (PARV) and calretinin (CALR) interneurons, whereas such levels remain stable in cholinergic and somatostatin interneurons. Thus, we speculate that the ability of cholinergic interneurons to maintain their levels of CREB after excitotoxic lesions is one of the factors determining their protection in Huntington's disease.