Differential contributions of Caenorhabditis elegans histone deacetylases to Huntingtin polyglutamine toxicity
Differential contributions of Caenorhabditis elegans histone deacetylases to Huntingtin polyglutamine toxicity
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DOI：
10.1523/jneurosci.3344-05.2006
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发表时间：
2006-03-08
影响因子：
5.3
通讯作者：
Hart, AC
中科院分区：
文献类型：
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作者：
Bates, EA;Victor, M;Hart, AC
在亨廷顿舞蹈病患者中，亨廷顿蛋白中聚谷氨酰胺束的扩张导致神经元变性和死亡，但聚谷氨酰胺介导的细胞死亡的分子机制尚不清楚。先前的研究表明，扩大的多谷氨酰胺束通过隔离富含谷氨酰胺的转录调节蛋白来改变转录，从而扰乱其功能。我们在表达人类亨廷顿蛋白片段的秀丽隐杆线虫神经元中验证了这一假设，该片段具有扩展的聚谷氨酰胺束（Htn-Q150）。使用功能等位基因缺失和RNA干扰（RNAi）检测秀丽隐杆线虫cAMP反应元件结合蛋白（CREB）、CREB结合蛋白（CBP）和组蛋白去乙酰化酶（hdac）在多谷氨酰胺诱导的神经变性中的作用。CREB （crh-1）的缺失或CBP （CBP -1）拷贝的缺失增强了秀丽隐杆线虫神经元的多聚谷氨酰胺毒性。然后使用功能等位基因缺失和RNAi来系统地降低每个秀丽隐杆线虫HDAC的功能。一般来说，敲低秀丽隐杆线虫HDACs可增强Htn-Q150的毒性，而敲低秀丽隐杆线虫hda-3可抑制Htn-Q150的毒性。hda-3的神经元表达恢复了Htn-Q150的毒性，提示秀丽隐杆线虫HDAC3 （hda-3）在神经元内促进Htn-Q150的退化。遗传上位性实验表明，HDA-3和CRH-1（秀丽隐杆线虫CREB同源物）在调节多聚谷氨酰胺毒性相关基因的转录方面是直接对立的。Hda-3功能丧失未能抑制hda-1/+组神经退行性变的增加；Htn-Q150动物，表明HDA-1和HDA-3在多谷氨酰胺毒性作用中具有不同的靶点和相反的作用。我们的研究结果表明，聚谷氨酰胺扩增会干扰CREB/CBP靶点的转录，而特异性靶向hdac将有助于减少相关的神经变性。
Expansion of a polyglutamine tract in the huntingtin protein causes neuronal degeneration and death in Huntington's disease patients, but the molecular mechanisms underlying polyglutamine-mediated cell death remain unclear. Previous studies suggest that expanded polyglutamine tracts alter transcription by sequestering glutamine rich transcriptional regulatory proteins, thereby perturbing their function. We tested this hypothesis in Caenorhabditis elegans neurons expressing a human huntingtin fragment with an expanded polyglutamine tract (Htn-Q150). Loss of function alleles and RNA interference (RNAi) were used to examine contributions of C. elegans cAMP response element-binding protein (CREB), CREB binding protein (CBP), and histone deacetylases (HDACs) to polyglutamine-induced neurodegeneration. Deletion of CREB (crh-1) or loss of one copy of CBP (cbp-1) enhanced polyglutamine toxicity in C. elegans neurons. Loss of function alleles and RNAi were then used to systematically reduce function of each C. elegans HDAC. Generally, knockdown of individual C. elegans HDACs enhanced Htn-Q150 toxicity, but knockdown of C. elegans hda-3 suppressed toxicity. Neuronal expression of hda-3 restored Htn-Q150 toxicity and suggested that C. elegans HDAC3 (HDA-3) acts within neurons to promote degeneration in response to Htn-Q150. Genetic epistasis experiments suggested that HDA-3 and CRH-1 (C. elegans CREB homolog) directly oppose each other in regulating transcription of genes involved in polyglutamine toxicity. hda-3 loss of function failed to suppress increased neurodegeneration in hda-1/+; Htn-Q150 animals, indicating that HDA-1 and HDA-3 have different targets with opposing effects on polyglutamine toxicity. Our results suggest that polyglutamine expansions perturb transcription of CREB/CBP targets and that specific targeting of HDACs will be useful in reducing associated neurodegeneration.