Toriumi Kazuya, Oma Yoko, Mimoto Ai, Futai Eugene, Sasagawa Noboru, Turk Boris, Ishiura Shoichi
Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
Genes Cells. 2009 Jun;14(6):751-7. doi: 10.1111/j.1365-2443.2009.01307.x. Epub 2009 May 22.
In recent years, several novel types of disorder caused by the expansion of triplet repeats in specific genes have been characterized; in the "polyalanine diseases", these expanded repeats result in proteins with aberrantly elongated polyalanine tracts. In this study, we fused expanded polyalanine tracts to yellow fluorescent protein to examine their physical interaction with mitochondria. Tracts containing more than 23 alanine repeats were found to physically associate with mitochondria, strongly suggesting that an interaction between polyalanine tracts and mitochondria is a contributing factor in the pathology of polyalanine diseases. Furthermore, in in vitro experiments, polyalanine tracts induced release of cytochrome c from mitochondria and caspase-3 activation, independently of the mitochondrial permeability transition pore. These results suggest that oligomerized polyalanine tracts might induce the rupture of the mitochondrial membrane, the subsequent release of cytochrome c, and apoptosis. This novel mechanism for polyalanine tract cytotoxicity might be common to the pathogenesis of all polyalanine diseases. Further investigation of this mechanism might aid the development of therapies for these diseases.
近年来，已经鉴定出几种由特定基因中三联体重复序列扩增引起的新型疾病；在“聚丙氨酸疾病”中，这些扩增的重复序列导致蛋白质具有异常延长的聚丙氨酸链。在本研究中，我们将扩增的聚丙氨酸链与黄色荧光蛋白融合，以检查它们与线粒体的物理相互作用。发现含有超过23个丙氨酸重复序列的链与线粒体发生物理关联，强烈表明聚丙氨酸链与线粒体之间的相互作用是聚丙氨酸疾病病理学中的一个促成因素。此外，在体外实验中，聚丙氨酸链诱导细胞色素c从线粒体释放并激活caspase-3，这与线粒体通透性转换孔无关。这些结果表明，寡聚化的聚丙氨酸链可能诱导线粒体膜破裂、随后细胞色素c释放和细胞凋亡。这种聚丙氨酸链细胞毒性的新机制可能是所有聚丙氨酸疾病发病机制所共有的。对这一机制的进一步研究可能有助于开发针对这些疾病的治疗方法。
