Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / toxicity*
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Analysis of Variance
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Animals
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cells, Cultured
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Cerebral Cortex / cytology
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Cytoplasm / drug effects
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Cytoplasm / metabolism
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Embryo, Mammalian
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Humans
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Immunoprecipitation / methods
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Neuroblastoma / pathology
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Neurons / cytology
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Neurons / drug effects*
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Peptide Fragments / toxicity*
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Phosphorylation / drug effects
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rats
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Rats, Wistar
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Signal Transduction / drug effects*
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TOR Serine-Threonine Kinases
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Transcription Factors
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Transfection / methods
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism*
Substances
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Amyloid beta-Peptides
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Ddit4 protein, rat
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Peptide Fragments
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RNA, Small Interfering
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Repressor Proteins
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TSC2 protein, human
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Transcription Factors
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Tsc2 protein, rat
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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amyloid beta-protein (1-42)
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Protein Kinases
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MTOR protein, human
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mTOR protein, rat
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TOR Serine-Threonine Kinases
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eIF-2 Kinase