Evidence of molecular links between PKR and mTOR signalling pathways in Aβ neurotoxicity: Role of p53, Redd1 and TSC2
Open accessAbstract
The control of translation is disturbed in Alzheimer's disease (AD). This study analysed the crosslink between the up regulation of double-stranded RNA-dependent-protein kinase (PKR) and the down regulation of mammalian target of rapamycin (mTOR) signalling pathways via p53, the protein Regulated in the Development and DNA damage response 1 (Redd1) and the tuberous sclerosis complex (TSC2) factors in two beta-amyloid peptide (Abeta) neurotoxicity models. In SH-SY5Y cells, Abeta42 induced an increase of P(T451)-PKR and of the ratio p66/(p66+p53) in nuclei and a physical interaction between these proteins. Redd1 gene levels increased and P(T1462)-TSC2 decreased. These disturbances were earlier in rat primary neurons with nuclear co-localization of Redd1 and PKR. The PKR gene silencing in SH-SY5Y cells prevented these alterations. p53, Redd1 and TSC2 could represent the molecular links between PKR and mTOR in Abeta neurotoxicity. PKR could be a critical target in a therapeutic program of AD.
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Transfection of PKR siRNA to Aβ42-treated SH-SY5Y cells significantly decreased the p66 isoform of p53, the transcriptional expression of Redd1 and increased the levels of phosphorylated TSC2.
“Recently, we showed that the transfection of PKR siRNA to Aβ42-treated SH-SY5Y cells significantly decreased the p66 isoform of p53, the transcriptional expression of Redd1 and increased the levels of phosphorylated TSC2 [129].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [129]
In 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 [129]
Cites
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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
Self-citation
- Authors
- Morel, M., Couturier, J., Pontcharraud, R., Gil, R., Fauconneau, B., Paccalin, M., & Page, G.
- Affiliations
- Université de Poitiers (FR)
- Corresponding author
- Page, Guylène
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 36
- Issue
- 1
- Pages
- 151-161
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2056636618
- Cited by
- 36
- References
- 9
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 5 · 2022: 1 · 2021: 2 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 7 · 2014: 4 · 2013: 3 · 2012: 2
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- green
- doaj.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- PKR, mTOR signaling, amyloid-beta toxicity, Alzheimer's disease, p53, REDD1, TSC2, double-stranded RNA-dependent protein kinase, translational regulation, SH-SY5Y cells, primary neurons, protein-protein interaction, therapeutic target
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, Analysis of Variance, Animals, Cell Nucleus, Cells, Cultured, Cerebral Cortex, Cytoplasm, Embryo, Mammalian, Gene Expression Regulation, Humans, Neuroblastoma, Neurons, Peptide Fragments, Phosphorylation, Protein Kinases, Repressor Proteins, Transcription Factors, Transfection, Signal Transduction, Tumor Suppressor Protein p53, Amyloid beta-Peptides, Rats, Wistar, eIF-2 Kinase, Tumor Suppressor Proteins, RNA, Small Interfering, Immunoprecipitation, Rats, TOR Serine-Threonine Kinases
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