Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington's disease.
Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington's disease.
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DOI：
10.1016/j.nbd.2010.08.017
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发表时间：
2011-01
影响因子：
6.1
通讯作者：
Messer, Anne
中科院分区：
文献类型：
--
作者：
Hathorn, Tyisha;Snyder-Keller, Abigail;Messer, Anne
关键词：
亨廷顿氏病（HD）是一种致命的常染色体显性神经退行性疾病，由亨廷顿基因（HTT）外显子1中聚谷氨酰胺（polyQ）重复扩增引起。这导致亨廷顿蛋白（htt）的错误折叠和积累，形成细胞核和细胞质包涵体。HD与基因表达失调以及线粒体功能障碍有关。我们假设，通过改善能量代谢所需基因的转录调节，HD运动表型也会得到改善。因此，我们研究了烟酰胺（NAM）的保护作用，烟酰胺是一种表征良好的水溶性B族维生素，是sirtuin1/ III类NAD+依赖性组蛋白去乙酰化酶（HDAC）的抑制剂。在本研究中，使用B6对微渗透泵和饮用水输送量进行了250mg NAM/kg/day的测试。HDR6/1转基因小鼠模型。两种给药方式的结果相似，没有毒性的证据。研究人员发现，NAM处理增加了脑源性神经营养因子（BDNF）和过氧化物酶体增殖物激活受体γ辅助激活因子1- α (PGC-1α)的mRNA水平，后者是线粒体生物发生的主要调节因子。BDNF蛋白水平也显著升高。此外，NAM治疗增加了HD小鼠的PGC-1α活化，指出了一种可能的治疗作用模式。关键的是，NAM治疗能够改善与HD表型相关的运动缺陷，通过开放场地、旋转杆和平衡木活动的时间过程进行测试。这些改进是实质性的，尽管不结盟运动似乎没有减少htt聚集，或防止后期体重减轻。因此，我们的研究得出结论，NAM或类似药物可能对HD运动功能障碍的临床治疗有益，但必须增加额外的治疗方法来对抗聚集表型和整体生理衰退。
Huntington’s disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by an expansion of the polyglutamine (polyQ) repeat in exon-1 in the Huntingtin gene (HTT). This results in misfolding and accumulation of the huntingtin (htt) protein, forming nuclear and cytoplasmic inclusions. HD is associated with dysregulation of gene expression as well as mitochondrial dysfunction. We hypothesized that by improving transcriptional regulation of genes necessary for energy metabolism, the HD motor phenotype would also improve. We therefore examined the protective effects of nicotinamide (NAM), a well-characterized water-soluble B vitamin that is an inhibitor of sirtuin1/class III NAD+-dependent histone deacetylase (HDAC). In this study, both mini-osmotic pumps and drinking water deliveries were tested at 250mg NAM/kg/day, using the B6.HDR6/1 transgenic mouse model. Results were similar for both modes of delivery, and there was no evidence of toxicity. We found that NAM treatment increased mRNA levels of brain-derived neurotrophic factor (BDNF), and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis. Protein levels of BDNF were also significantly increased. In addition, NAM treatment increased PGC-1α activation in HD mice, pointing to a possible mode of action as a therapeutic. Critically, NAM treatment was able to improve motor deficits associated with the HD phenotype, tested as time courses of open field, rotarod, and balance beam activities. These improvements were substantial, despite the fact that NAM did not appear to reduce htt aggregation, or to prevent late-stage weight loss. Our study therefore concludes that NAM or similar drugs may be beneficial in clinical treatment of the motor dysfunctions of HD, while additional therapeutic approaches must be added to combat the aggregation phenotype and overall physiological decline.
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