Bax-like protein Drob-1 protects neurons from expanded polyglutamine-induced toxicity in Drosophila
Bax-like protein Drob-1 protects neurons from expanded polyglutamine-induced toxicity in Drosophila
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DOI：
10.1038/sj.emboj.7600721
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发表时间：
2005-07-20
期刊：
影响因子：
11.4
通讯作者：
Miura, M
中科院分区：
文献类型：
--
作者：
Senoo-Matsuda, N;Igaki, T;Miura, M
Bcl-2家族蛋白通过线粒体凋亡途径调节细胞死亡。在这里，我们表明，果蝇类Bcl-2家族蛋白Drob-1维持线粒体功能，以保护细胞免受神经变性。Drob-1的泛神经元敲低导致成年果蝇的运动活性降低和寿命缩短。RNAi介导的Drob-I的下调或Drob-I拮抗剂Buffy的过表达强烈增强了聚谷氨酰胺诱导的泛素化蛋白的积累和随后的神经变性。此外，Drob-1的异位表达抑制了由扩展的聚谷氨酰胺引起的果蝇的神经变性和过早死亡。Drob-1敲低降低细胞ATP水平，并增强呼吸道蛋白诱导的线粒体缺陷，如膜电位（Δ psi（m））的丧失、形态异常和复合物I+III和复合物II+III活性的降低以及细胞死亡。总之，这些结果表明，Drob-I是神经元细胞功能所必需的，并且Drob-I通过调节线粒体稳态来保护神经元免受扩展的聚谷氨酰胺介导的神经变性。
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 (Delta psi(m)), 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.