生命过程小分子调节剂的研究:Small-molecule regulators of autophagy identified by an image-based high-throughput screen

  • 关键字: Small-molecule regulators of autophagy 发布者:Lihong Zhang*, Dawei Ma*, and Junying Yuan 发布时间:2009-03-02 18:03:59 点击数: 4549次

Proc. Natl. Acad. Sci. 2007, 104, 19023-19028.
Small-molecule regulators of autophagy identified by an image-based high-throughput screen
Lihong Zhang*, Jia Yu*, Heling Pan*, Ping Hu*, Yan Hao*, Wenqing Cai*, Hong Zhu†, Albert D. Yu†, Xin Xie‡, Dawei Ma*,§, and Junying Yuan†,§
*State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Department of Cell Biology, Harvard Medical School, Boston, MA 02115; and National Center for Drug Screening, Shanghai 201203, China
Abstract: Autophagy is a lysosome-dependent cellular catabolic mechanism mediating the turnover of intracellular organelles and long-lived proteins. Reduction of autophagy activity has been shown to lead to the accumulation of misfolded proteins in neurons and may be involved in chronic neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. To explore the mechanism of autophagy and identify small molecules that can activate it, we developed a series of high-throughput image-based screens for small-molecule regulators of autophagy. This series of screens allowed us to distinguish compounds that can truly induce autophagic degradation from those that induce the accumulation of autophagosomes as a result of causing cellular damage or blocking downstream lysosomal functions. Our analyses led to the identification of eight compounds that can induce autophagy and promote long-lived protein degradation. Interestingly, seven of eight compounds are FDA-approved drugs for treatment of human diseases. Furthermore, we show that these compounds can reduce the levels of expanded polyglutamine repeats in cultured cells. Our studies suggest the possibility that some of these drugs may be useful for the treatment of Huntington's and other human diseases associated with the accumulation of misfolded proteins.