ATP controls neuronal apoptosis triggered by microtubule breakdown or potassium deprivation

Background: Early loss of neurites followed by delayed damage of neuronal s omata is a feature of several neurodegenerative diseases. Death by apoptosi s would ensure the rapid removal of injured neurons, whereas conditions tha t prevent apoptosis may facilitate the persistence of damaged cells and fav or inflammation and disease progression. Materials and Methods: Cultures of cerebellar granule cells (CGC) were trea ted with microtubule disrupting agents. These compounds induced an early de generation of neurites followed by apoptotic destruction of neuronal somata . The fate of injured neurons was followed after co-exposure to caspase inh ibitors or agents that decrease intracellular ATP (deoxyglucose, S-nitrosog lutathione, 1-methyl-4-phenylpyridinium). We examined the implications of e nergy loss for caspase activation, exposure of phagocytosis markers, and lo ng-term persistence of damaged cells. Results: In CGC exposed to colchicine or nocodazole, axodendritic degenerat ion preceded caspase activation and apoptosis. ATP-depleting agents or prot ein synthesis inhibition prevented caspase activation, translocation of the phagocytosis marker, phosphatidylserine, and apoptotic death. However, the y did not affect the primary neurite loss. Repletion of ATP by enhanced gly colysis restored all apoptotic features. Peptide inhibitors of caspases als o prevented the apoptotic changes in the cell bodies, although the axodendr itic net was lost. Under this condition cell demise still occurred 48 hr la ter in a caspase-independent manner and involved plasma membrane lysis at t he latest stage. Conclusions: Inhibition of the apoptotic machinery by drugs, energy depriva tion, or endogenous mediators may result in the persistence and subsequent lysis of injured neurons. In vivo, this may favor the onset of inflammatory processes and perpetuate neurodegeneration.