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Tissue inhibitor of metalloproteinases-3 (TIMP-3) expression is increased during serum deprivation-induced neuronal apoptosis in vitro and in the G93A mouse model of amyotrophic lateral sclerosis: a potential modulator of Fas-mediated apoptosis.

Lee, JK; Shin, JH; Suh, J; Choi, IS; Ryu, KS; Gwag, BJ
Neurobiology of disease, 30(2):174-185, 2008
Journal Title
Neurobiology of disease
Cortical neurons deprived of serum undergo apoptosis that is sensitive to inhibitors of macromolecule synthesis. Proteomic analysis revealed differential expression of 49 proteins in cortical neurons 8 h after serum deprivation. Tissue inhibitor of metalloproteinases-3 (TIMP-3), a pro-apoptotic protein in various cancer cells, was increased during serum deprivation-induced apoptosis (SDIA), but not during necrosis induced by excitotoxicity or oxidative stress. Levels of TIMP-3 were markedly increased in degenerating motor neurons in a transgenic model of familial amyotrophic lateral sclerosis. The TIMP-3 expression was accompanied by increase in Fas-FADD interaction, activated caspase-8, and caspase-3 during SDIA and in vulnerable spinal cord of the ALS mouse. SDIA and activation of the Fas pathway were prevented by addition of an active MMP-3. Timp-3 deletion by RNA interference attenuated SDIA in N2a cells. These findings provide evidence that TIMP-3 is an upstream mediator of neuronal apoptosis and likely contributes to neuronal loss in neurodegenerative diseases such as amyotrophic lateral sclerosis.
MeSH terms
Alanine/geneticsAmino Acid Substitution/geneticsAmyotrophic Lateral Sclerosis/enzymology*Amyotrophic Lateral Sclerosis/geneticsAnimalsAntigens, CD95/physiology*Apoptosis/drug effectsApoptosis/physiology*Cell Line, TumorCells, CulturedCulture Media, Serum-Free/pharmacology*Disease Models, AnimalFemaleGene Expression Regulation, Enzymologic/drug effectsGene Expression Regulation, Enzymologic/physiologyGlycine/geneticsHumansMaleMiceMice, Inbred C57BLMice, TransgenicNeurons/drug effectsNeurons/enzymology*Superoxide Dismutase/biosynthesisSuperoxide Dismutase/geneticsTissue Inhibitor of Metalloproteinase-3/biosynthesis*Tissue Inhibitor of Metalloproteinase-3/genetics*Tissue Inhibitor of Metalloproteinase-3/physiologyUp-Regulation/genetics*
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Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
곽, 병주
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