Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motoneurons in the spinal cord and brain stem. We have characterized motoneuron death in transgenic mice carrying the mutant human copper/zinc superoxide dismutase, as a model for familial ALS. Previous studies have shown the involvement of mitochondria in nerve cell demise in these animals. We report here an early cleavage of caspase-12, residing in the endoplasmic reticulum (ER), in the spinal cord during the course of the disease. Apart from caspase-12, caspase-9, and caspase-3 were activated in the transgenic ALS mice. Staining with an antibody for nitrotyrosine, as a marker for oxidative stress, showed a large increase in the ALS mice. The results indicate that oxidative and ER induced stress causing caspase-12 activation are involved in neuronal death and disease progression in ALS. Caspase-12 and the ER pathway for cell death may constitute potential novel targets for the treatment of ALS.
Department of Neuroscience, Unit of Neurobiology, Uppsala University, Biomedical Centre, Box 587, S-751 23 Uppsala, Sweden.
Hanna
H
Wootz
Inga
I
Hansson
Laura
L
Korhonen
Ulla
U
Näpänkangas
Dan
D
Lindholm
D000222:Adaptation, Physiological / Q000502:physiology*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D051379:Mice; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism
D013482:Superoxide Dismutase; C506444:CASP12 protein, human; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases