Proteasome inhibitors prevent cytochrome c release during apoptosis but not in excitotoxic death of cerebellar granule neurons.
In order to find out whether and how proteasomes participate in the processes leading cerebellar granule cells to death either in necrosis, due to glutamate neurotoxicity, or in apoptosis, due to K(+) shift, we measured the three proteasome activities by using specific fluorescent probes and investigated the effect of several proteasome inhibitors, including MG132, on the cytochrome c release taking place in the early phase of both apoptosis and necrosis. We show that differently from apoptosis, the early phase of necrosis does not require proteasome activation. Inhibition of proteasome activity can prevent cytochrome c release in cerebellar granule cells undergoing apoptosis, thus improving cell survival, but not necrosis. These findings show that proteasomes play an important role in the early phase of apoptosis but not that of necrosis, and that these two types of cell death differ from each other in their mechanism of cytochrome c release.
Bobba
Antonella
A
Centro di Studio sui Mitocondri e Metabolismo Energetico, CNR, Via Amendola 165/A, 70126, Bari, Italy. csmmab03@area.ba.cnr.it
Canu
Nadia
N
Atlante
Anna
A
Petragallo
Vito
V
Calissano
Pietro
P
Marra
Ersilia
E
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003546:Cysteine Endopeptidases; D003574:Cytochrome c Group / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005456:Fluorescent Dyes; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009336:Necrosis; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017208:Rats, Wistar
D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D009097:Multienzyme Complexes; D009498:Neurotoxins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex