Caspase-1 activation of caspase-6 in human apoptotic neurons.
Active caspase-6 (Csp-6) induces cell death in primary cultures of human neurons and is abundant in the neuropathological lesions of Alzheimer's disease. However, the mode of Csp-6 activation is not known. Here, we show that the Csp-1 inhibitor, Z-YVAD-fmk specifically prevents activation of Csp-6 and cell death in human neurons. A transient increase in Csp-1-like activity and an increase in the p23Csp-1 subunit occur early after serum deprivation. Recombinant active Csp-1 (R-Csp-1) cleaves recombinant and neuronal pro-Csp-6 in vitro resulting in Csp-6 activity. However, R-Csp-1 does not induce cell death when microinjected in human neurons despite the inhibition of serum-deprivation induced cell death with a Csp-1 dominant negative construct. These results show that Csp-1 is an upstream positive regulator of Csp-6-mediated cell death in primary human neurons. Furthermore, these results suggest that the activation of Csp-1 must be accompanied by an apoptotic insult to induce Csp-6-mediated cell death.
Guo
H
H
Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, Quebec, Canada.
Pétrin
D
D
Zhang
Y
Y
Bergeron
C
C
Goodyer
C G
CG
LeBlanc
A C
AC
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D020170:Caspase 1 / Q000378:metabolism*; D053178:Caspase 6; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D015151:Immunoblotting; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D011994:Recombinant Proteins; C460579:benzyloxycarbonyltyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone; C505514:CASP6 protein, human; D053178:Caspase 6; D020169:Caspases; D020170:Caspase 1