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Human Molecular Genetics Advance Access published online on February 23, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl036
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 5, 2005
Revised February 2, 2006
Accepted February 15, 2006

Article

Rapamycin pre-treatment protects against apoptosis

Brinda Ravikumar 1, Zdenek Berger 2, Coralie Vacher 1, Cahir J O'Kane 3, and David C Rubinsztein 1 *

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

* To whom correspondence should be addressed.
David C Rubinsztein, E-mail: dcr1000{at}hermes.cam.ac.uk


  Abstract

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 (1, 2). This protective effect of rapamycin was attributed to enhanced clearance of the mutant protein via autophagy (1, 2). 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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