Letter abstract
Nature Chemical Biology 3, 331 - 338 (2007)
Published online: 7 May 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
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 e-mail: stuart_schreiber@harvard.edu
Correspondence to: David C Rubinsztein1 e-mail: dcr1000@cam.ac.uk
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Stimulating the cell's appetite for itselfNature Chemical Biology News and Views (01 Jun 2007)
Huntingtin aggregates ask to be eatenNature Genetics News and Views (01 Jun 2004)
See all 4 matches for News And ViewsRESEARCH
Novel targets for Huntington's disease in an mTOR-independent autophagy pathwayNature Chemical Biology Article (01 May 2008)
Novel targets for Huntington's disease in an mTOR-independent autophagy pathwayNature Chemical Biology Article (01 May 2008)
See all 33 matches for Research
