Rapamycin pre-treatment protects against apoptosis.
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.
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Cambridge, UK.
Brinda
B
Ravikumar
Zdenek
Z
Berger
Coralie
C
Vacher
Cahir J
CJ
O'Kane
David C
DC
Rubinsztein
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D019556:COS Cells; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
D045304:Cytochromes c; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D020123:Sirolimus