Neuronal phosphorylated RNA-dependent protein kinase in Creutzfeldt-Jakob disease.
Paquet, Claire Bose, Anindita Polivka, Marc Peoc'h, Katell Brouland, Jean Philippe Keohane, Catherine Hugon, Jacques Gray, Françoise
Paquet, Claire
Bose, Anindita
Polivka, Marc
Peoc'h, Katell
Brouland, Jean Philippe
Keohane, Catherine
Hugon, Jacques
Gray, Françoise
Advisors
Editors
Other Contributors
Date
2009-02
Date Submitted
Keywords
Other Subjects
Subject Mesh
Aged
Aged, 80 and over
Apoptosis
Brain
Caspase 3
Cell Nucleus
Creutzfeldt-Jakob Syndrome
Female
Glial Fibrillary Acidic Protein
Gliosis
Humans
Immunohistochemistry
In Situ Nick-End Labeling
Male
Middle Aged
Nerve Degeneration
Neurons
Phosphorylation
Prions
Stress, Physiological
eIF-2 Kinase
Aged, 80 and over
Apoptosis
Brain
Caspase 3
Cell Nucleus
Creutzfeldt-Jakob Syndrome
Female
Glial Fibrillary Acidic Protein
Gliosis
Humans
Immunohistochemistry
In Situ Nick-End Labeling
Male
Middle Aged
Nerve Degeneration
Neurons
Phosphorylation
Prions
Stress, Physiological
eIF-2 Kinase
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
Publisher
Abstract
The mechanisms of neuronal apoptosis in Creutzfeldt-Jakob disease (CJD) and their relationship to accumulated prion protein (PrP) are unclear. A recent cell culture study showed that intracytoplasmic PrP may induce phosphorylated RNA-dependent protein kinase (PKR(p))-mediated cell stress. The double-stranded RNA protein kinase PKR is a proapoptotic and stress kinase that accumulates in degenerating neurons in Alzheimer disease. To determine whether neuronal apoptosis in human CJD is associated with activation of the PKR(p) signaling pathway, we assessed in situ end labeling and immunocytochemistry for PrP, glial fibrillary acidic protein, CD68, activated caspase 3, and phosphorylated PKR (Thr451) in samples of frontal, occipital, and temporal cortex, striatum, and cerebellum from 6 patients with sporadic CJD and 5 controls. Neuronal immunostaining for activated PKR was found in all CJD cases. The most staining was in nuclei and, in contrast to findings in Alzheimer disease, cytoplasmic labeling was not detected. Both the number and distribution of PKR(p)-positive neurons correlated closely with the extent of neuronal apoptosis, spongiosis, astrocytosis, and microglial activation and with the phenotype and disease severity. There was no correlation with the type, topography, or amount of extracellular PrP deposits. These findings suggest that neuronal apoptosis in human CJD may result from PKR(p)-mediated cell stress and are consistent with recent studies supporting a pathogenic role for intracellular or transmembrane PrP.
Language
en
ISSN
0022-3069
eISSN
ISBN
DOI
10.1097/NEN.0b013e318196cd7c
PMID
19151623