Expression of expanded polyglutamine proteins suppresses the activation of transcription factor NFκB

Abstract

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 downregulated the NFκB-dependent transcriptional activity. The expression of expanded polyglutamine proteins increased the stability and the levels of IκB-α and its phosphorylated derivatives. We have also found that various NFκB subunits and IκB-α aberrantly interacted with the expanded polyglutamine proteins and associated with their aggregates. Finally, we have shown that several NFκB-dependent genes are down-regulated in the expanded polyglutamine protein-expressing cells and down-regulation of NFκB activity enhances expanded polyglutamine protein-induced cell death. Because the NFκB 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. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.