Caspase requirement for neuronal apoptosis and neurodegeneration

The execution of the apoptotic programme involves a relatively few pathways that converge on activation of the caspase family of proteases. However, i ncreasing evidence indicates that apoptotic-like features can he found also when cells are treated with inhibitors of caspases. This has posed questio ns as to whether death with apoptotic features can still occur in a caspase -independent way, and whether caspase inhibitors mag then be used to preven t excess apoptosis in disease. Metabolic defects, loss of neuronal connecti vity and cell loss characterise several neurodegenerative diseases, Targeti ng excessive cell demise may be one therapeutic strategy. However, loss of connectivity and neurite regression may not be part of the apoptotic progra mme, and degenerating neurons might use multiple execution pathways, In add ition, metabolic defects leading to ATP depiction can preclude caspase acti vation and consequently switch execution of cell death towards necrosis. Th e possibility of inhibiting apoptosis as strategy to treat neurodegenerativ e disease is discussed in this review.