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.
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.
Lee
Jae Keun
JK
Research Institute for Neural Science and Technology, Ajou University School of Medicine, Suwon, South Korea.
Shin
Jin Hee
JH
Suh
JaeHong
J
Choi
In Sun
IS
Ryu
Keun Sil
KS
Gwag
Byoung Joo
BJ
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*
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