細胞的自我吞食是一種在演化上被保留下來的機制,，這是一種細胞“吞食”自己的細胞質的一種生物學過程,。如今,，研究人員發(fā)現(xiàn)一種能夠增加細胞自我吞食作用的小分子，這種小分子也許是治療亨廷頓癥等疾病的一種潛在藥物,。這一研究成果發(fā)表在6月號的《自然—化學生物學》（Nature Chemical Biology）期刊上,。
科學家們已經(jīng)知道，具有聚集傾向的蛋白質是神經(jīng)退化性疾病的主要誘因,，而細胞的自我吞食對去除聚集傾向的蛋白質至關重要,，因此,，增加細胞的自我吞食作用是治療這類疾病的潛在戰(zhàn)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,，但這種分子負責調節(jié)大量的細胞生理過程，因此,，如果將之作為治療靶標,，將會有相當多的副作用。
David Rubinsztein,、Stuart Schreiber和同事對一系列酵母進行化學掃描,，鑒別出3種能夠增加細胞自我吞食作用的小分子。他們指出,，這些化合物能夠抑制哺乳動物細胞和亨廷頓疾病模型動物黑腹果蠅的疾病進展,，從而為這類疾病的治療提供了一種重要的治療途徑。（生物谷援引科學時報）
原始出處:
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: [email protected]
Correspondence to: David C Rubinsztein1 Email: [email protected]
