Atypical role of proximal caspase-8 in truncated Tau-induced neurite regression and neuronal cell death.
Abnormal Tau protein is known to be closely associated with several neurodegenerative diseases. Previously, we showed that Tau was cleaved by caspase-3 to generate the cleavage product lacking the C-terminus (DeltaTau-1) during neuronal cell death. Here we characterized caspase-8-dependent neurotoxicity of the truncated Tau. Introduction of DeltaTau-1 into primary hippocampal neurons induced loss of neurites in a caspase-dependent manner. Caspase-8 and -6 were proteolytically activated during DeltaTau-1-triggered neuronal cell death, which was suppressed by IETD-fmk, caspase-8 inhibitor. Direct targeting of caspase-8 and its associated FADD with antisense approaches and transient expression of their dominant-negative mutants reduced DeltaTau-1-induced apopotosis. Cells deficient in caspase-8, but not caspase-3, became sensitized to DeltaTau-1-mediated toxicity upon reconstitution with caspase-8. In addition, ectopic expression of mitochondrial antiapoptotic Bcl-2, Bcl-X(L), or inactive caspase-9 short form suppressed DeltaTau-1 toxicity. These results suggest that the truncated Tau protein activates proximal caspase-8 through FADD as a necessary step leading to neuronal cell death and neurite regression, contributing to the progression of abnormal Tau-associated neurodegeneracy.
Chung
Chul-Woong
CW
Department of Life Science, Kwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, 500-712 Gwangju, Korea.
Hong
Yeon-Mi
YM
Song
Sungmin
S
Woo
Ha-Na
HN
Choi
Yun-Hee
YH
Rohn
Troy
T
Jung
Yong-Keun
YK
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism* / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D016375:Antisense Elements (Genetics); D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D016875:tau Proteins; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases