Wei Yang1,2, Li-Feng Yang1, Zhi-Qi Song1, Syed Zahid Ali Shah1, Yong-Yong Cui1, Chao-Si Li1, Hua-Fen Zhao1, Hong-Li Gao1, Xiang-Mei Zhou1, De-Ming Zhao1. 1. National Animal Transmissible Spongiform Encephalopathy Laboratory and Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China. 2. Hebei Institute of Animal Science and Veterinary Medicine, Baoding, China.
Abstract
AIMS: The proline-rich Akt substrate of 40-kDa (PRAS40) protein is a direct inhibitor of mTORC1 and an interactive linker between the Akt and mTOR pathways. The mammalian target of rapamycin (mTOR) is considered to be a central regulator of cell growth and metabolism. Several investigations have demonstrated that abnormal mTOR activity may contribute to the pathogenesis of several neurodegenerative disorders and lead to cognitive deficits. METHODS: Here, we used the PrP peptide 106-126 (PrP106-126 ) in a cell model of prion diseases (also known as transmissible spongiform encephalopathies, TSEs) to investigate the mechanisms of mTOR-mediated cell death in prion diseases. RESULTS: We have shown that, upon stress caused by PrP106-126 , the mTOR pathway activates and contributes to cellular apoptosis. Moreover, we demonstrated that PRAS40 down-regulates mTOR hyperactivity under stress conditions and alleviates neurotoxic prion peptide-induced apoptosis. The effect of PRAS40 on apoptosis is likely due to an mTOR/Akt signaling. CONCLUSION: PRAS40 inhibits mTORC1 hyperactivation and plays a key role in protecting cells against neurotoxic prion peptide-induced apoptosis. Thus, PRAS40 is a potential therapeutic target for prion disease.
AIMS: The proline-rich Akt substrate of 40-kDa (PRAS40) protein is a direct inhibitor of mTORC1 and an interactive linker between the Akt and mTOR pathways. The mammalian target of rapamycin (mTOR) is considered to be a central regulator of cell growth and metabolism. Several investigations have demonstrated that abnormal mTOR activity may contribute to the pathogenesis of several neurodegenerative disorders and lead to cognitive deficits. METHODS: Here, we used the PrP peptide 106-126 (PrP106-126 ) in a cell model of prion diseases (also known as transmissible spongiform encephalopathies, TSEs) to investigate the mechanisms of mTOR-mediated cell death in prion diseases. RESULTS: We have shown that, upon stress caused by PrP106-126 , the mTOR pathway activates and contributes to cellular apoptosis. Moreover, we demonstrated that PRAS40 down-regulates mTORhyperactivity under stress conditions and alleviates neurotoxicprion peptide-induced apoptosis. The effect of PRAS40 on apoptosis is likely due to an mTOR/Akt signaling. CONCLUSION: PRAS40 inhibits mTORC1hyperactivation and plays a key role in protecting cells against neurotoxicprion peptide-induced apoptosis. Thus, PRAS40 is a potential therapeutic target for prion disease.
Authors: Attila Garami; Fried J T Zwartkruis; Takahiro Nobukuni; Manel Joaquin; Marta Roccio; Hugo Stocker; Sara C Kozma; Ernst Hafen; Johannes L Bos; George Thomas Journal: Mol Cell Date: 2003-06 Impact factor: 17.970
Authors: Kristina S Kovacina; Grace Y Park; Sun Sik Bae; Andrew W Guzzetta; Erik Schaefer; Morris J Birnbaum; Richard A Roth Journal: J Biol Chem Date: 2003-01-10 Impact factor: 5.157