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The Journal of Neuroscience, December 15, 2000, 20(24):9119-9125

Delaying Caspase Activation by Bcl-2: A Clue to Disease Retardation in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Slobodanka Vukosavic¹, Leonidas Stefanis^{1, 2}, Vernice Jackson-Lewis¹, Christelle Guégan¹, Norma Romero¹, Caiping Chen¹, Michel Dubois-Dauphin³, and Serge Przedborski^{1, 2}

Departments of ¹ Neurology and ² Pathology, Columbia University, New York, New York 10032, and ³ Department of Psychiatry, HUG Belle-Idee, University of Geneva School of Medicine, 1225 Geneva, Switzerland

Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant copper/zinc superoxide dismutase (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, herein 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 and its produced -actin cleavage fragments are found in apoptotic neurons in the anterior horn of the spinal cord of affected transgenic mSOD1 mice; although such neurons are few, their scarcity should not undermine the potential importance of apoptosis in the overall mSOD1-related neurodegeneration. Overexpression of the anti-apoptotic protein Bcl-2 attenuates neurodegeneration and delays activation of the caspases and fragmentation of -actin. These data demonstrate that caspase activation occurs in this mouse model of ALS during neurodegeneration. Our study also suggests that modulation of caspase activity may provide protective benefit in the treatment of ALS, a view that is consistent with our recent demonstration of caspase inhibition extending the survival of transgenic mSOD1 mice.

Key words: amyotrophic lateral sclerosis; apoptosis; Bcl-2; caspase; superoxide dismutase; neuronal death

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20249119-07$05.00/0

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