Expression of expanded polyglutamine proteins suppresses the activation of transcription factor NFkappaB.
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.
Goswami
Anand
A
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122050, India.
Dikshit
Priyanka
P
Mishra
Amit
A
Nukina
Nobuyuki
N
Jana
Nihar Ranjan
NR
D000818:Animals; D019556:COS Cells; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D013997:Time Factors; D014162:Transfection
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D010455:Peptides; D000072000:NF-KappaB Inhibitor alpha; C097188:polyglutamine