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Characterization of the caspase cascade in a cell culture model of SOD1‐related familial amyotrophic lateral sclerosis: expression, activation and therapeutic effects of inhibition

There is increasing evidence that apoptosis or a similar programmed cell death pathway is the mechanism of cell death responsible for motor neurone degeneration in amyotrophic lateral sclerosis. Knowledge of the relative importance of different caspases in the cell death process is at present incomplete. In addition, there is little information on the critical point of the death pathway when the process of dying becomes irreversible. In this study, using the well‐established NSC34 motor neurone‐like cell line stably transfected with empty vector, normal or mutant human Cu‐Zn superoxide dismutase (SOD1), we have characterized the activation of the caspase cascade in detail, revealing that the activation of caspases‐9, ‐3 and ‐8 are important in motor neurone death and that the presence of mutant SOD1 causes increased activation of components of the apoptotic cascade under both basal culture conditions and following oxidative stress induced by serum withdrawal. Activation of the caspases identified in the cellular model has been confirmed in the G93A SOD1 transgenic mice. Furthermore, investigation of the effects of anti‐apoptotic neuroprotective agents including specific caspase inhibitors, minocycline and nifedipine, have supported the importance of the mitochondrion‐dependent apoptotic pathway in the death process and revealed that the upstream caspase cascade needs to be inhibited if useful neuro‐protection is to be achieved.