Endoplasmic reticulum (ER) stress elicits protective responses of chaperone induction and translational suppression and, when unimpeded, leads to caspase-mediated apoptosis. Alzheimer's disease-linked mutations in presenilin-1 (PS-1) reportedly impair ER stress-mediated protective responses and enhance vulnerability to degeneration. We used cleavage site-specific antibodies to characterize the cysteine protease activation responses of primary mouse cortical neurons to ER stress and evaluate the influence of a PS-1 knock-in mutation on these and other stress responses. Two different ER stressors lead to processing of the ER-resident protease procaspase-12, activation of calpain, caspase-3, and caspase-6, and degradation of ER and non-ER protein substrates. Immunocytochemical localization of activated caspase-3 and a cleaved substrate of caspase-6 confirms that caspase activation extends into the cytosol and nucleus. ER stress-induced proteolysis is unchanged in cortical neurons derived from the PS-1 P264L knock-in mouse. Furthermore, the PS-1 genotype does not influence stress-induced increases in chaperones Grp78/BiP and Grp94 or apoptotic neurodegeneration. A similar lack of effect of the PS-1 P264L mutation on the activation of caspases and induction of chaperones is observed in fibroblasts. Finally, the PS-1 knock-in mutation does not alter activation of the protein kinase PKR-like ER kinase (PERK), a trigger for stress-induced translational suppression. These data demonstrate that ER stress in cortical neurons leads to activation of several cysteine proteases within diverse neuronal compartments and indicate that Alzheimer's disease-linked PS-1 mutations do not invariably alter the proteolytic, chaperone induction, translational suppression, and apoptotic responses to ER stress.
Endoplasmic Reticulum Stress-induced Cysteine Protease Activation in Cortical Neurons
R. Siman,D. Flood,G. Thinakaran,R. Neumar
Published 2001 in Journal of Biological Chemistry
ABSTRACT
PUBLICATION RECORD
- Publication year
2001
- Venue
Journal of Biological Chemistry
- Publication date
2001-11-30
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- apoptotic neurodegeneration
Stress-associated neuronal degeneration proceeding through apoptotic death pathways.
Aliases: apoptotic degeneration
- calpain activation
Activation of the calcium-dependent cysteine protease calpain as part of the stress response examined in the cells.
Aliases: calpain
- caspase-3 activation
Conversion of procaspase-3 to its active protease form during the stress response.
Aliases: activated caspase-3, caspase 3 activation
- caspase-6 activation
Conversion of procaspase-6 to its active protease form and cleavage of a caspase-6 substrate during the stress response.
Aliases: activated caspase-6, caspase 6 activation
- cortical neurons
Primary mouse neurons derived from the cerebral cortex and used as the main neuronal cell type in the experiments.
Aliases: primary mouse cortical neurons
- endoplasmic reticulum stress
A cellular stress state caused by perturbation of protein folding or homeostasis in the endoplasmic reticulum, used here as the experimental trigger.
Aliases: ER stress
- fibroblasts
Non-neuronal connective tissue cells included here for comparison with cortical neurons in the stress response assays.
- grp78/bip
An ER chaperone protein used as a marker of the unfolded protein response and stress-induced chaperone induction.
Aliases: BiP, Grp78
- grp94
An ER-resident chaperone protein measured as part of the stress-induced chaperone response.
- perk activation
Activation of the protein kinase RNA-like endoplasmic reticulum kinase involved in translational control during ER stress.
Aliases: protein kinase PKR-like ER kinase activation, PERK
- presenilin-1 p264l knock-in mutation
An Alzheimer's disease-linked Presenilin-1 point mutation introduced into the mouse genome for comparison with wild type.
Aliases: PS-1 P264L knock-in mutation, PS-1 P264L
- procaspase-12 processing
Proteolytic cleavage of the ER-resident zymogen procaspase-12 into processed forms during stress.
Aliases: caspase-12 processing, procaspase 12 processing
REFERENCES
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