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Science:雷帕霉素可中止一种罕见的婴幼儿疾病

来源:EurekAlert 2013-11-15 19:38

据一项新的研究报道,一种影响婴幼儿的罕见的神经退行性病变的致命性影响可在一种现有药物的帮助下而推迟发生。

Leigh综合征源自一种会破坏线粒体的突变;线粒体是细胞产生能量的细胞器。一个出生时带有这种突变的孩子常常会在一年内出现Leigh综合征的衰弱的症状--并在此后仅数年内就死亡。

尽管不存在治愈Leigh综合征的方法,先前的研究显示,具有类似这样疾病的线粒体缺陷的酵母菌会在阻断mTOR通路——该通路已知会促成一系列的疾病——的信号转导时存活较长的时间。这使得Simon C. Johnson及其同事开始探索当他们在一个Leigh综合征的小鼠模型中抑制mTOR信号转导时会发生什么情况。

研究人员使用了一种已知会在其途径中停止mTOR信号转导的药物——这是一种叫做雷帕霉素的免疫抑制剂。他们发现,将其注射到非常年幼的小鼠体内可显著地延缓与Leigh综合征有关的神经系统症状的进展,特别是当小鼠在10天大时开始每日接受该药物。确实,这些小鼠中活的最长的小鼠可维持存活的时间会比那些仅仅隔日接受雷帕霉素的小鼠长3倍。

这表明,雷帕霉素或其它抑制mTOR的药物可被探索作为对Leigh综合征--及也许还有其它线粒体疾病的治疗药物。但是首先必须确立对雷帕霉素在小鼠中减轻Leigh综合征机制的更为详尽的理解。(生物谷Bioon.com)

生物谷推荐的英文摘要

Science         DOI: 10.1126/science.1244360

mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh Syndrome

Simon C. Johnson1, Melana E. Yanos1,2, Ernst-Bernhard Kayser3, Albert Quintana4, Maya Sangesland1, Anthony Castanza1, Lauren Uhde1, Jessica Hui1, Valerie Z. Wall1, Arni Gagnidze1, Kelly Oh1, Brian M. Wasko1, Fresnida J. Ramos1, Richard D. Palmiter4, Peter S. Rabinovitch1, Philip G. Morgan3, Margaret M. Sedensky3, Matt Kaeberlein1,*

Mitochondrial dysfunction contributes to numerous health problems including neurological and muscular degeneration, cardiomyopathies, cancer, diabetes, and pathologies of aging. Severe mitochondrial defects can result in childhood disorders such as Leigh syndrome, for which there are no effective therapies. Here, we report that rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, robustly enhances survival and attenuates disease progression in a mouse model of Leigh syndrome. Administration of rapamycin to these mice, which are deficient in the mitochondrial respiratory chain subunit NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4), delays onset of neurological symptoms, reduces neuroinflammation, and prevents brain lesions. While the precise mechanism of rescue remains to be determined, rapamycin induces a metabolic shift toward amino acid catabolism and away from glycolysis, alleviating the buildup of glycolytic intermediates. This therapeutic strategy may prove relevant for a broad range of mitochondrial diseases.

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