Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Y. Li, T. Yokota, V. Gama, T. Yoshida, J. A. Gomez, K. Ishikawa, H. Sasaguri, H. Y. Cohen, D. A. Sinclair, H. Mizusawa, S. Matsuyama

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87 Scopus citations

Abstract

Polyglutamine (polyQ) diseases, such as Huntington's disease and Machado-Joseph disease (MJD), are caused by gain of toxic function of abnormally expanded polyQ tracts. Here, we show that expanded polyQ of ataxin-3 (Q79C), a gene that causes MJD, stimulates Ku70 acetylation, which in turn dissociates the proapoptotic protein Bax from Ku70, thereby promoting Bax activation and subsequent cell death. The Q79C-induced cell death was significantly blocked by Ku70 or Bax-inhibiting peptides (BIPs) designed from Ku70. Furthermore, expression of SIRT1 deacetylase and the addition of a SIRT1 agonist, resveratrol, reduced Q79C toxicity. In contrast, mimicking acetylation of Ku70 abolished the ability of Ku70 to suppress Q79C toxicity. These results indicate that Bax and Ku70 acetylation play important roles in Q79C-induced cell death, and that BIP may be useful in the development of therapeutics for polyQ diseases.

Original languageEnglish
Pages (from-to)2058-2067
Number of pages10
JournalCell Death and Differentiation
Volume14
Issue number12
DOIs
StatePublished - Dec 2007

Bibliographical note

Funding Information:
Acknowledgements. We thank Dr. Akira Kakizuka for providing ataxin-3-expressing plasmid, Dr. Hideki Nishitoh for recombinant adenoviruses encoding Q79C and Q35C, Dr. Shinichirou Imai for providing mouse SIRT1 cDNA and Dr. Hideki Mochizuki for providing mouse tissue sample treated with MPTP as positive control of activated Bax. We also thank Ms. Keiko Kaneko, Ms. Kanae Yonetsu and Ms. Iku Sudo for their technical help. This work was supported in part by a grant from the 21st Century COE Program on Brain Integration and its Disorders to Tokyo Medical and Dental University (to YL and HM), Japan Foundation for Neuroscience and Mental Health (to YL, TY and HM), National Institute of Health (USA) (P20CA10373 to SM) and American Heart Association (to VG (predoctoral fellowship), JG (predoctoral fellowship) and SM (Grant-in-Aid)).

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