细胞的自我吞食是一种在演化上被保留下来的机制，这是一种细胞“吞食”自己的细胞质的一种生物学过程。如今，研究人员发现一种能够增加细胞自我吞食作用的小分子，这种小分子也许是治疗亨廷顿症等疾病的一种潜在药物。这一研究成果发表在6月号的《自然—化学生物学》（Nature Chemical Biology）期刊上。
科学家们已经知道，具有聚集倾向的蛋白质是神经退化性疾病的主要诱因，而细胞的自我吞食对去除聚集倾向的蛋白质至关重要，因此，增加细胞的自我吞食作用是治疗这类疾病的潜在战略之一。然而，雷帕霉素是目前已知的唯一能增加自我吞食作用的小分子，但这种分子负责调节大量的细胞生理过程，因此，如果将之作为治疗靶标，将会有相当多的副作用。
David Rubinsztein、Stuart Schreiber和同事对一系列酵母进行化学扫描，鉴别出3种能够增加细胞自我吞食作用的小分子。他们指出，这些化合物能够抑制哺乳动物细胞和亨廷顿疾病模型动物黑腹果蝇的疾病进展，从而为这类疾病的治疗提供了一种重要的治疗途径。（生物谷援引科学时报）
原始出处:
Nature Chemical Biology 3, 331-338 (2007)
doi:10.1038/nchembio883
Small molecules enhance autophagy and reduce toxicity in Huntington's disease models
Sovan Sarkar1,6, Ethan O Perlstein2,3,6, Sara Imarisio4, Sandra Pineau1, Axelle Cordenier4, Rebecca L Maglathlin3, John A Webster3, Timothy A Lewis3, Cahir J O'Kane4, Stuart L Schreiber3,5 & David C Rubinsztein1
Abstract
The target of rapamycin proteins regulate various cellular processes including autophagy1, which may play a protective role in certain neurodegenerative and infectious diseases2. Here we show that a primary small-molecule screen in yeast yields novel small-molecule modulators of mammalian autophagy. We first identified new small-molecule enhancers (SMER) and inhibitors (SMIR) of the cytostatic effects of rapamycin in Saccharomyces cerevisiae. Three SMERs induced autophagy independently of rapamycin in mammalian cells, enhancing the clearance of autophagy substrates such as mutant huntingtin and A53T -synuclein, which are associated with Huntington's disease and familial Parkinson's disease, respectively3, 4, 5. These SMERs, which seem to act either independently or downstream of the target of rapamycin, attenuated mutant huntingtin-fragment toxicity in Huntington's disease cell and Drosophila melanogaster models, which suggests therapeutic potential. We also screened structural analogs of these SMERs and identified additional candidate drugs that enhanced autophagy substrate clearance. Thus, we have demonstrated proof of principle for a new approach for discovery of small-molecule modulators of mammalian autophagy.
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
Howard Hughes Medical Institute, the Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
These authors contributed equally to this work.
Correspondence to: Stuart L Schreiber3,5 Email: stuart_schreiber@harvard.edu
Correspondence to: David C Rubinsztein1 Email: dcr1000@cam.ac.uk
