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J. Biol. Chem., Vol. 281, Issue 48, 37017-37024, December 1, 2006

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Expression of Expanded Polyglutamine Proteins Suppresses the Activation of Transcription Factor NFB^*

Anand Goswami, Priyanka Dikshit¹, Amit Mishra¹, Nobuyuki Nukina, and Nihar Ranjan Jana²

From the Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122 050, India and Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

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 NFB-dependent transcriptional activity. The expression of expanded polyglutamine proteins increased the stability and the levels of IB- and its phosphorylated derivatives. We have also found that various NFB subunits and IB- aberrantly interacted with the expanded polyglutamine proteins and associated with their aggregates. Finally, we have shown that several NFB-dependent genes are down-regulated in the expanded polyglutamine protein-expressing cells and down-regulation of NFB activity enhances expanded polyglutamine protein-induced cell death. Because the NFB 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.

Received for publication, August 23, 2006 , and in revised form, October 5, 2006.

^* This work was supported by the Dept. of Biotechnology, Government of India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a research fellowship from the Council of Scientific and Industrial Research, Government of India.

² To whom correspondence should be addressed: Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122 050, India. Tel.: 91-124-2338922; Fax: 91-124-2338910; E-mail: nihar{at}nbrc.ac.in.

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