Delaying caspase activation by Bcl-2: A clue to disease retardation in a transgenic mouse model of amyotrophic lateral sclerosis

Molecular mechanisms of apoptosis may participate in motor neuron degenerat ion produced by mutant copper/zinc superoxide dismutase (mSOD1), the only p roven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, h erein we show that the spinal cord of transgenic mSOD1 mice is the site of the sequential activation of caspase-1 and caspase-3. Activated caspase-3 a nd its produced beta -actin cleavage fragments are found in apoptotic neuro ns in the anterior horn of the spinal cord of affected transgenic mSOD1 mic e; although such neurons are few, their scarcity should not undermine the p otential importance of apoptosis in the overall mSOD1-related neurodegenera tion. Overexpression of the anti-apoptotic protein Bcl-2 attenuates neurode generation and delays activation of the caspases and fragmentation of beta -actin. These data demonstrate that caspase activation occurs in this mouse model of ALS during neurodegeneration. Our study also suggests that modula tion of caspase activity may provide protective benefit in the treatment of ALS, a view that is consistent with our recent demonstration of caspase in hibition extending the survival of transgenic mSOD1 mice.