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  • The EMBO Journal (2005) 24, 2700 - 2713
  • doi:10.1038/sj.emboj.7600721

Published online: 7 July 2005

Bax-like protein Drob-1 protects neurons from expanded polyglutamine-induced toxicity in Drosophila

Nanami Senoo-Matsuda1,2,a, Tatsushi Igaki3 and Masayuki Miura1

  1. Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
  2. Laboratory for Cell Recovery Mechanisms, RIKEN Brain Science Institute, Wako, Saitama, Japan
  3. Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT, USA

Correspondence to:

Masayuki Miura, Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: +81 3 5841 4860; Fax: +81 3 5841 4867; E-mail: miura@mol.f.u-tokyo.ac.jp

aPresent address: Department of Genetics and Development, Collage of Physicians and Surgeons, Columbia University, 701 West 168th Street, New York, NY 10032, USA

Received 10 September 2004; Accepted 31 May 2005

Bcl-2 family proteins regulate cell death through the mitochondrial apoptotic pathway. Here, we show that the Drosophila Bax-like Bcl-2 family protein Drob-1 maintains mitochondrial function to protect cells from neurodegeneration. A pan-neuronal knockdown of Drob-1 results in lower locomotor activity and a shorter lifespan in adult flies. Either the RNAi-mediated downregulation of Drob-1 or overexpression of Drob-1 antagonist Buffy strongly enhances the polyglutamine-induced accumulation of ubiquitinated proteins and subsequent neurodegeneration. Furthermore, ectopic expression of Drob-1 suppresses the neurodegeneration and premature death of flies caused by expanded polyglutamine. Drob-1 knockdown decreases cellular ATP levels, and enhances respiratory inhibitor-induced mitochondrial defects such as loss of membrane potential (Deltapsim), morphological abnormalities, and reductions in activities of complex I+III and complex II+III, as well as cell death. Taken together, these results suggest that Drob-1 is essential for neuronal cell function, and that Drob-1 protects neurons from expanded polyglutamine-mediated neurodegeneration through the regulation of mitochondrial homeostasis.

  • Keywords:

    • Bcl-2,
    • cell death,
    • mitochondrial function,
    • neurodegeneration,
    • polyglutamine disease