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Death‐signalling cascade in mouse cerebellar granule neurons
Author(s) -
Tanabe Hiroki,
Eguchi Yutaka,
Shimizu Shigeomi,
Martinou JeanClaude,
Tsujimoto Yoshihide
Publication year - 1998
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1998.00148.x
Subject(s) - microbiology and biotechnology , caspase , programmed cell death , biology , neurotrophic factors , cycloheximide , signal transduction , neurodegeneration , apoptosis , chemistry , biochemistry , protein biosynthesis , medicine , receptor , disease
Molecular mechanisms of neuronal cell death are still largely unknown. In the present study, the signal transduction pathway of cell death in cerebellar granule neurons was examined by employing various death‐preventative agents. When death was induced by the depletion of serum and a depolarizing level of potassium, transient increase in active c‐Jun, mitochondrial membrane potential (Δψ) loss, activation of caspase‐3 (‐like) proteases, and nuclear condensation and fragmentation were observed. The protein synthesis inhibitor cycloheximide blocked all these phenomena, whereas RNA synthesis inhibitor actinomycin‐D, survival factor such as insulin‐like growth factor‐1, brain‐derived neurotrophic factor, high K + (25 m m ) and overproduced antiapoptotic protein Bcl‐2, prevented Δψ loss, caspase activation, and nuclear change, but not an increase in active c‐Jun. The caspase inhibitor z‐Asp‐CH 2 ‐DCB (carbobenzoxy‐ l ‐aspartyl‐α‐[(2,6‐dichlorobenzoyl) oxy]methane) only inhibited activation of caspases and nuclear change. These results suggest that the death signal in cerebellar granule neurons is sequentially transduced in the order of c‐Jun activation, de novo RNA synthesis, mitochondrial Δψ loss, activation of caspase‐3 (‐like) proteases and nuclear change.