Curcumin enhances the polyglutamine-expanded truncated N-terminal huntingtin-induced cell death by promoting proteasomal malfunction

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Abstract

Formation of neuronal intranuclear inclusions of the disease proteins that are ubiquitinated and often associated with various proteasome components is the major hallmark of the polyglutamine diseases. Curcumin is a polyphenolic compound having anti-inflammatory, anti-tumor, and anti-oxidative properties. Recently, curcumin has been reported to suppress the amyloid-β accumulation, oxidative damage, and inflammation in the transgenic mice model of Alzheimer’s disease. Here, we found that the treatment of curcumin increases the polyglutamine-expanded truncated N-terminal huntingtin (mutant huntingtin) aggregation and mutant huntingtin-dependent cell death. Curcumin also causes rapid proteasomal malfunction in the mutant huntingtin expressing cells in comparison with normal glutamine repeat expressing cells. Finally, we show that N-acetyl cysteine (NAC), a potent antioxidant, reverted the curcumin-induced mutant huntingtin aggregation and proteasomal malfunction in the mutant huntingtin expressing cells. NAC also protects curcumin-induced cell death. Our result suggests that curcumin promotes mutant huntingtin-induced cell death by mimicking proteasomal dysfunction.

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Materials and methods

Materials. Curcumin, lactacystin, proteasome substrate, N-acetyl cysteine (NAC), rabbit polyclonal ubiquitin antibody, mouse monoclonal β-tubulin antibody, and all cell culture reagents were obtained from Sigma. LipofectAMINE 2000 and ponasterone A were obtained from Invitrogen, Mouse monoclonal anti-HA was obtained from Roche, and AP-conjugated anti-mouse and anti-rabbit IgG were from Vector Laboratories. Ubiquitin construct (with HA tag) was a kind gift from Dr. R. Takahashi, RIKEN Brain

Curcumin enhances the expanded polyglutamine protein-induced cell death

To test the possible effect of curcumin on the expanded polyglutamine protein-induced cell death we used stable and inducible cell lines that express truncated N-terminal huntingtin (tNhtt) fused with EGFP containing 16 and 150 glutamine residues. The cell lines were named HD 16Q and HD 150Q and their corresponding expressed proteins were named tNhtt-16Q and tNhtt-150Q. The cell lines were induced with 1 μM of ponasterone A for 2 days and then exposed to different doses of curcumin for 10 h. The

Discussion

Curcumin has long been used as a popular dietary spice and herbal medicine in several Southeastern countries. Different evidence suggests that curcumin has chemopreventive and anti-tumor activities because of its ability to induce apoptosis [19], [20], [21], [22]. The question was if there is any protective role of curcumin in Huntington’s disease and other polyglutamine diseases as were earlier shown in Alzheimer’s disease. The answer we got was not in affirmative. We found that curcumin

Acknowledgments

This work was supported by the Department of Biotechnology, Government of India. P.D. and A.M. were supported by research fellowship from Council of Scientific and Industrial Research, Government of India.

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