Evidence of molecular links between PKR and mTOR signalling pathways in Aβ neurotoxicity: Role of p53, Redd1 and TSC2

• Main Authors: Milena Morel, Julien Couturier, Raymond Pontcharraud, Roger Gil, Bernard Fauconneau, Marc Paccalin, Guylène Page
• Format: Article
• Language: English
• Published: Elsevier 2009-10-01
• Series: Neurobiology of Disease
• Subjects: Alzheimer's disease; PKR; p53; Redd1; TSC2; mTOR
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996109001776
• ISSN: 1095-953X

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 β-amyloid peptide (Aβ) neurotoxicity models. In SH-SY5Y cells, Aβ42 induced an increase of PT451-PKR and of the ratio p66/(p66+p53) in nuclei and a physical interaction between these proteins. Redd1 gene levels increased and PT1462-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 Aβ neurotoxicity. PKR could be a critical target in a therapeutic program of AD.