Involvement of double‐stranded RNA‐dependent protein kinase and phosphorylation of eukaryotic initiation factor‐2α in neuronal degeneration
Open accessAbstract
Inhibition of protein translation plays an important role in apoptosis. While double‐stranded RNA‐dependent protein kinase (PKR) is named as it is activated by double‐stranded RNA produced by virus, its activation induces an inhibition of protein translation and apoptosis via the phosphorylation of the eukaryotic initiation factor 2α (eIF2α). PKR is also a stress kinase and its levels increase during ageing. Here we show that PKR activation and eIF2α phosphorylation play a significant role in apoptosis of neuroblastoma cells and primary neuronal cultures induced by the β‐amyloid (Aβ) peptides, the calcium ionophore A23187 and flavonoids. The phosphorylation of eIF2α and the number of apoptotic cells were enhanced in over‐expressed wild‐type PKR neuroblastoma cells exposed to Aβ peptide, while dominant‐negative PKR reduced eIF2α phosphorylation and apoptosis induced by Aβ peptide. Primary cultured neurons from PKR knockout mice were also less sensitive to Aβ peptide toxicity. Activation of PKR and eIF2α pathway by Aβ peptide are triggered by an increase in intracellular calcium because the intracellular calcium chelator BAPTA‐AM significantly reduced PKR phosphorylation. Taken together, these results reveal that PKR and eIF2α phosphorylation could be involved in the molecular signalling events leading to neuronal apoptosis and death and could be a new target in neuroprotection.
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Aβ neurotoxicity is associated with an increased PKR and eIF2α phosphorylation linked to increased intracellular calcium and caspase-8 activation following Aβ exposure in vitro.
“Another report demonstrated in vitro that Aβ neurotoxicity was associated with an increased PKR and eIF2α phosphorylation linked to increased intracellular calcium and caspase-8 activation following Aβ exposure [28, 30].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [30]
The Discussion reports increased PKR and eIF2α phosphorylation during Aβ-induced neuronal apoptosis and links pathway activation to increased intracellular calcium. The time-course section reports caspase-3 activity after Aβ exposure, not caspase-8 activation; that part of the claim is unsupported by this source. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn cells deficient for PKR or containing a dominant-negative form, there is substantial resistance to apoptosis.
“Conversely, in cells deficient for the kinase or containing a dominant-negative form, there is substantial resistance to apoptosis [30, 61, 63].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [30]
The section on vulnerability to Aβ peptide toxicity reports significantly fewer apoptotic cells among neurons expressing dominant-negative PKR. The PKR-knockout results (p. 1221) likewise show a much smaller increase in apoptosis after Aβ exposure, but the Discussion says those neurons did not entirely escape toxicity. The evidence concerns Aβ-induced neuronal apoptosis, not resistance to apoptosis generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn Alzheimer's disease, eIF2a and p53 are targets of PKR.
“In AD, eIF2a and p53 are targets of PKR [28, 30, 97, 102, 129].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [30]
The paper’s Abstract states that activated PKR phosphorylates eIF2α, and its experimental findings link PKR activity to eIF2α phosphorylation in amyloid-β-treated neuronal cultures. The cited passages do not identify p53 as a PKR target, and the experiments use neuronal models rather than establishing both targets in people with Alzheimer’s disease. (LLM, conf=0.86)
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Research works printed but not linked: 5
- Aktas H., Fluckiger R., Acosta J. A., Savage J. M., Palakurthi S. S. and Halperin J. A. (1998) Depletion of intracellular Ca2+ stores, phosphorylation of eIF2alpha, and sustained inhibition of transla- tion initiation mediate the anticancer effects of clotrimazole. Proc. Natl Acad. Sci. USA 95, 8280-8285.
- Der S. D., Yang Y. L., Weissmann C. and Williams B. R. (1997) A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc. Natl Acad. Sci. USA 94, 3279-3283.
- Frerichs K. U., Smith C. B., Brenner M., DeGracia D. J., Krause G. S., Marrone L., Dever T. E. and Hallenbeck J. M. (1998) Suppression of protein synthesis in brain during hibernation involves inhibition of protein initiation and elongation. Proc. Natl Acad. Sci. USA 95, 14511-14516.
- R. C.-C. Chang et al. Ó 2002 International Society for Neurochemistry, Journal of Neurochemistry, 83, 1215-1225 14714159, 2002, 5, · DOI
- PKR and eIF2a in neurodegeneration 1225 Ó 2002 International Society for Neurochemistry, Journal of Neurochemistry, 83, 1215-1225 14714159, 2002, 5, · DOI
Cited by
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Cheung, Y.-T., Lau, W. K.-W., Yu, M.-S., Lai, C. S.-W., Yeung, S.-C., So, K.-F., & Chang, R. C.-C. (2009) · NeuroToxicology · doi:10.1016/j.neuro.2008.11.001 · Cited by 576 · see citing works
Self-citationTranslational control in synaptic plasticity and cognitive dysfunction
Buffington, S. A., Huang, W., & Costa-Mattioli, M. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014100 · Cited by 348 · see citing works
Chang, R. C. C., Wong, A. K. Y., Ng, H.-K., & Hugon, J. (2002) · NeuroReport · doi:10.1097/00001756-200212200-00011 · Cited by 289 · see citing works
Self-citationTranslational Control in the Brain in Health and Disease
Sossin, W. S., & Costa-Mattioli, M. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a032912 · Cited by 138 · see citing works
PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease
Morel, M., Couturier, J., Lafay‐Chebassier, C., Paccalin, M., & Page, G. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00849.x · Cited by 47 · see citing works
- Authors
- Chang, R. C., Suen, K., Ma, C., Elyaman, W., Ng, H., & Hugon, J.
- Affiliations
- University of Hong Kong (HK)
- Chinese University of Hong Kong (HK)
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2002-11-19
- Volume
- 83
- Issue
- 5
- Pages
- 1215-1225
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1934976150
- Cited by
- 180
- References
- 0
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 8 · 2021: 5 · 2020: 5 · 2019: 11 · 2018: 8 · 2017: 6 · 2016: 9 · 2015: 8 · 2014: 7 · 2013: 7 · 2012: 6
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- Cleveland Clinic
- Cleveland Clinic Foundation
- University of Hong Kong
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- double-stranded RNA-dependent protein kinase, PKR, eIF2α phosphorylation, neuronal apoptosis, neurodegeneration, amyloid-beta, intracellular calcium, neuroprotection, neuroblastoma cells, flavonoids, A23187, stress kinases
- MeSH terms
- Calcimycin, Animals, Calcium, Cell Count, Humans, Ionophores, Mice, Inbred C57BL, Neuroblastoma, Neurons, Peptide Fragments, Phosphorylation, Quercetin, Eukaryotic Initiation Factor-2, Amyloid beta-Peptides, Rats, Sprague-Dawley, Apoptosis, Genistein, eIF-2 Kinase, Mice, Rats
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