title: PRAS40 alleviates neurotoxic prion peptide-induced apoptosis via mTOR-AKT signaling.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.|Hebei Institute of Animal Science and Veterinary Medicine, Baoding, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Li-Feng
authors.initials: LF
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Zhi-Qi
authors.initials: ZQ
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Syed Zahid Ali
authors.initials: SZA
authors.lastname: Shah
authors.affiliation: 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.
authors.forename: Yong-Yong
authors.initials: YY
authors.lastname: Cui
authors.affiliation: 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.
authors.forename: Chao-Si
authors.initials: CS
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Hua-Fen
authors.initials: HF
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Hong-Li
authors.initials: HL
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Xiang-Mei
authors.initials: XM
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: De-Ming
authors.identifier: http://orcid.org/0000-0002-9638-5958
authors.initials: DM
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011257:Pregnancy Proteins / Q000633:toxicity*; D017096:Prion Diseases / Q000188:drug therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection
chemical_list: D010750:Phosphoproteins; C057074:Plfr protein, mouse; D011257:Pregnancy Proteins; D017382:Reactive Oxygen Species; C508191:proline-rich Akt substrate, 40 kDa protein, mouse; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: PI3K-Akt-mTOR signaling; apoptosis; mammalian target of rapamycin (mTOR); negative feedback mechanism; prion diseases; proline-rich Akt substrate of 40-kDa (PRAS40)