Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model.

By M. Li, V. Ona, C. Guégan, M. Chen, V. Jackson-Lewis, L. Andrews, A. Olszewski, P. Stieg, J. P. Lee, S. Przedborski and 1 more. Science, 2000

728 citations recorded by the source corpus.

Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an animal model of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To test a new therapeutic strategy for ALS, we examined the effect of caspase inhibition in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 (mSOD1(G93A)). Intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor, delays disease onset and mortality. Moreover, zVAD-fmk inhibits caspase-1 activity as well as caspase-1 and caspase-3 mRNA up-regulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. Caspases play an instrumental role in neurodegeneration in transgenic mSOD1(G93A) mice, which suggests that caspase inhibition may have a protective role in ALS.

Subfields: Genetics, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/ee7e727aa61bfa8151bb48e8b20da9d590efae18

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Mark P. Mattson

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Citations in the corpus

Nitric oxide‐induced mitochondrial fission is regulated by dynamin‐related GTPases in neurons (2006, background): “Both caspase-dependent and independent pathways appear to operate in the neuronal loss in neurodegenerative disorders (Li et al, 2000; Leist and Jaattela, 2001; Friedlander, 2003; Cregan et al, 2004).”
Apoptosis in neurodegenerative disorders (2000, background): “The involvement of apoptosis in ALS is further suggested by the fact that overexpression of Bcl-2 and administration of caspase inhibitors delays degeneration and death of motor neurons in Cu/Zn-SOD mutant mic”
Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice (2002, methodology): “Because the above-mentioned factors are important in amyotrophic lateral sclerosis (ALS), we tested minocycline in mice with AL”
Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease (2002, methodology): “Ventral midbrain content of mature murine IL-1 was done as described using an enzyme-linked immunosorbend assay kit specific for this cytokine (R & D Systems, Minneapolis, MN) (Li et al., 2000).”
The physiology and pathophysiology of nitric oxide in the brain. (2005, background): “Motor neurons die due to apoptotic processes (Martin, 1999) triggered by the activation of caspases 1 and 3 (Li et al., 2000).”
Molecular mechanisms of cell death in neurological diseases (2021, background): “The onset of symptoms and terminal illness were also delayed in SOD1 mice by administration of the broad spectrum caspase inhibitor zVAD-fmk [35], overexpression of BCL-2 [36] or the absence of the apoptosis effectors BAX and BAK [37].”