title: 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.
abstract: 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.
authors.affiliation: Research Institute for Neural Science and Technology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Jae Keun
authors.initials: JK
authors.lastname: Lee
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Shin
authors.forename: JaeHong
authors.initials: J
authors.lastname: Suh
authors.forename: In Sun
authors.initials: IS
authors.lastname: Choi
authors.forename: Keun Sil
authors.initials: KS
authors.lastname: Ryu
authors.forename: Byoung Joo
authors.initials: BJ
authors.lastname: Gwag
mesh_terms: D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics*; D019014:fas Receptor / Q000502:physiology*
chemical_list: D016895:Culture Media, Serum-Free; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D019014:fas Receptor; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000409:Alanine; D005998:Glycine