Goswami Anand, Dikshit Priyanka, Mishra Amit, Nukina Nobuyuki, Jana Nihar Ranjan
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122050, India.
J Biol Chem. 2006 Dec 1;281(48):37017-24. doi: 10.1074/jbc.M608095200. Epub 2006 Oct 6.
A major pathological hallmark of the polyglutamine diseases is the formation of neuronal intranuclear inclusions of the disease proteins that are ubiquitinated and often associated with various transcription factors, chaperones, and proteasome components. However, how the expanded polyglutamine proteins or their aggregates elicit complex pathogenic responses in the neuronal cells is not fully understood. Here, we have demonstrated that the expression of expanded polyglutamine proteins down-regulated the NFkappaB-dependent transcriptional activity. The expression of expanded polyglutamine proteins increased the stability and the levels of IkappaB-alpha and its phosphorylated derivatives. We have also found that various NFkappaB subunits and IkappaB-alpha aberrantly interacted with the expanded polyglutamine proteins and associated with their aggregates. Finally, we have shown that several NFkappaB-dependent genes are down-regulated in the expanded polyglutamine protein-expressing cells and down-regulation of NFkappaB activity enhances expanded polyglutamine protein-induced cell death. Because the NFkappaB pathway plays a very important role in cell survival, altered regulation of this pathway in expanded polyglutamine protein-expressing cells might be linked with the disease pathogenesis.
多聚谷氨酰胺疾病的一个主要病理标志是疾病蛋白在神经元核内形成包含体，这些包含体被泛素化，并且常常与各种转录因子、分子伴侣和蛋白酶体成分相关。然而，扩展的多聚谷氨酰胺蛋白或其聚集体如何在神经元细胞中引发复杂的致病反应尚未完全明确。在此，我们证明了扩展的多聚谷氨酰胺蛋白的表达下调了NFκB依赖性转录活性。扩展的多聚谷氨酰胺蛋白的表达增加了IκB-α及其磷酸化衍生物的稳定性和水平。我们还发现，各种NFκB亚基和IκB-α与扩展的多聚谷氨酰胺蛋白异常相互作用并与其聚集体相关。最后，我们表明在表达扩展的多聚谷氨酰胺蛋白的细胞中，几个NFκB依赖性基因被下调，并且NFκB活性的下调增强了扩展的多聚谷氨酰胺蛋白诱导的细胞死亡。由于NFκB途径在细胞存活中起着非常重要的作用，在表达扩展的多聚谷氨酰胺蛋白的细胞中该途径的调节改变可能与疾病发病机制有关。
