1. ¹Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
2. ²Departments of Medicine and Pharmacology, Case Western Reserve University, Cleveland, OH, USA
3. ³Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
4. ⁴Paul F. Glenn Laboratories for the Molecular Biology of Aging, Department of Pathology, Harvard Medical School, Boston, MA, USA

Correspondence: T Yokota, Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan. Tel: +81 3 5803 5234; Fax: +81 3 5803 0169; E-mail: tak-yokota.nuro@tmd.ac.jp; S Matsuyama, Departments of Medicine and Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA. Tel: 216 368 5832; Fax: 216 368 8919; E-mail: shigemi.matsuyama@case.edu

⁵These authors contributed equally to this work

Received 22 December 2006; Revised 23 July 2007; Accepted 23 July 2007; Published online 21 September 2007.

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.