Bax-like protein Drob-1 protects neurons from expanded polyglutamine-induced toxicity in Drosophila.
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.
Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Nanami
N
Senoo-Matsuda
Tatsushi
T
Igaki
Masayuki
M
Miura
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015536:Down-Regulation; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D005124:Eye Abnormalities / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010455:Peptides / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D051028:bcl-2-Associated X Protein
D029721:Drosophila Proteins; D008565:Membrane Proteins; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C404322:debcl protein, Drosophila; C097188:polyglutamine; D000255:Adenosine Triphosphate