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.
Morel
Milena
M
Research Group on Brain Aging, GReViC EA 3808, University of Poitiers, 6 rue de la Milétrie BP 199, 86034 Poitiers Cedex, France.
Couturier
Julien
J
Pontcharraud
Raymond
R
Gil
Roger
R
Fauconneau
Bernard
B
Paccalin
Marc
M
Page
Guylène
G
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D014162:Transfection / Q000379:methods; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C000632146:Ddit4 protein, rat; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C075222:amyloid beta-protein (1-42); D011494:Protein Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase