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Human Molecular Genetics Advance Access originally published online on February 23, 2006
Human Molecular Genetics 2006 15(7):1209-1216; doi:10.1093/hmg/ddl036
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Rapamycin pre-treatment protects against apoptosis

Brinda Ravikumar1, Zdenek Berger1,2, Coralie Vacher1, Cahir J. O'Kane2 and David C. Rubinsztein1,*

1Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK and 2Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK

* To whom correspondence should be addressed. Email: dcr1000{at}hermes.cam.ac.uk

Received December 5, 2005; Revised February 2, 2006; Accepted February 15, 2006

Macroautophagy (generally referred to as autophagy) mediates the bulk degradation of cytoplasmic contents, including proteins and organelles, in lysosomes. Rapamycin, a lipophilic, macrolide antibiotic, induces autophagy by inactivating the protein mammalian target of rapamycin (mTOR). We previously showed that rapamycin protects against mutant huntingtin-induced neurodegeneration in cell, fly and mouse models of Huntington's disease [Ravikumar, B., Duden, R. and Rubinsztein, D.C. (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet., 11, 1107–1117, Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O'Kane, C.J. et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet., 36, 585–595]. This protective effect of rapamycin was attributed to enhanced clearance of the mutant protein via autophagy [Ravikumar, B., Duden, R. and Rubinsztein, D.C. (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet., 11, 1107–1117, Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O'Kane, C.J. et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet., 36, 585–595]. Here, we show that rapamycin may have additional cytoprotective effects—it protects cells against a range of subsequent pro-apoptotic insults and reduces paraquat toxicity in Drosophila. This protection can be accounted for by enhanced clearance of mitochondria by autophagy, thereby reducing cytosolic cytochrome c release and downstream caspase activation after pro-apoptotic insults. Thus, rapamycin (pro-autophagic) treatment may be useful in certain disease conditions (including various neurodegenerative diseases) where a slow but increased rate of apoptosis is evident, even if they are not associated with overt aggregate formation.


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