Caspase-1 is Activated in Neural Cells and Tissue with Amyotrophic Lateral Sclerosis-Associated Mutations in Copper-Zinc Superoxide Dismutase

The mechanism by which mutations in the superoxide dismutase (SOD1) gene cause motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS) is unknown. Recent reports that neuronal death in SOD1-familial ALS is apoptotic have not documented activation of cell death genes. We present evi...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-12, Vol.95 (26), p.15763-15768
Main Authors: Pasinelli, Piera, Borchelt, David R., Houseweart, Megan K., Cleveland, Don W., Brown, Robert H.
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - enzymology
Amyotrophic Lateral Sclerosis - genetics
Animals
Apoptosis
B lymphocytes
Biological Sciences
Caspase 1 - metabolism
Cell Death
Cell Line
Cell lines
Cell Survival
Cells
Cellular differentiation
Enzyme Activation
Humans
Ice
Interleukin-1 - biosynthesis
Mice
Mutagenesis
Mutation
Neurology
Neurons
Neurons - cytology
Neurons - enzymology
Recombinant Proteins - metabolism
Secretion
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Transfection
Viability
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Summary:The mechanism by which mutations in the superoxide dismutase (SOD1) gene cause motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS) is unknown. Recent reports that neuronal death in SOD1-familial ALS is apoptotic have not documented activation of cell death genes. We present evidence that the enzyme caspase-1 is activated in neurons expressing mutant SOD1 protein. Proteolytic processing characteristic of caspase-1 activation is seen both in spinal cords of transgenic ALS mice and neurally differentiated neuroblastoma (line N2a) cells with SOD1 mutations. This activation of caspase-1 is enhanced by oxidative challenge (xanthine/xanthine oxidase), which triggers cleavage and secretion of the interleukin 1β converting enzyme substrate, pro-interleukin 1β , and induces apoptosis. This N2a culture system should be an instructive in vitro model for further investigation of the proapoptotic properties of mutant SOD1.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.26.15763