Evidence of molecular links between PKR and mTOR signalling pathways in Abeta neurotoxicity: role of p53, Redd1 and TSC2.

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.
Mesh Terms:
Amyloid beta-Peptides, Analysis of Variance, Animals, Cell Nucleus, Cells, Cultured, Cerebral Cortex, Cytoplasm, Embryo, Mammalian, Gene Expression Regulation, Humans, Immunoprecipitation, Neuroblastoma, Neurons, Peptide Fragments, Phosphorylation, Protein Kinases, RNA, Small Interfering, Rats, Rats, Wistar, Repressor Proteins, Signal Transduction, TOR Serine-Threonine Kinases, Transfection, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, eIF-2 Kinase
Neurobiol. Dis.
Date: Oct. 01, 2009
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