title: Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR.
abstract: Transmissible spongiform encephalopathies are fatal neurodegenerative diseases caused by the conversion of prion protein (PrP(C)) into an infectious isoform (PrP(Sc)). How this event leads to pathology is not fully understood. Here we demonstrate that protein synthesis in neurons is enhanced via PrP(C) interaction with stress-inducible protein 1 (STI1). We also show that neuroprotection and neuritogenesis mediated by PrP(C)-STI1 engagement are dependent upon the increased protein synthesis mediated by PI3K-mTOR signaling. Strikingly, the translational stimulation mediated by PrP(C)-STI1 binding is corrupted in neuronal cell lines persistently infected with PrP(Sc), as well as in primary cultured hippocampal neurons acutely exposed to PrP(Sc). Consistent with this, high levels of eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation were found in PrP(Sc)-infected cells and in neurons acutely exposed to PrP(Sc). These data indicate that modulation of protein synthesis is critical for PrP(C)-STI1 neurotrophic functions, and point to the impairment of this process during PrP(Sc) infection as a possible contributor to neurodegeneration.
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, 04023-062 São Paulo, Brazil.
authors.forename: Martín
authors.initials: M
authors.lastname: Roffé
authors.forename: Flávio Henrique
authors.initials: FH
authors.lastname: Beraldo
authors.forename: Romina
authors.initials: R
authors.lastname: Bester
authors.forename: Max
authors.initials: M
authors.lastname: Nunziante
authors.forename: Christian
authors.initials: C
authors.lastname: Bach
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mancini
authors.forename: Sabine
authors.initials: S
authors.lastname: Gilch
authors.forename: Ina
authors.initials: I
authors.lastname: Vorberg
authors.forename: Beatriz A
authors.initials: BA
authors.lastname: Castilho
authors.forename: Vilma Regina
authors.initials: VR
authors.lastname: Martins
authors.forename: Glaucia Noeli Maroso
authors.initials: GN
authors.lastname: Hajj
mesh_terms: D000818:Animals; D002460:Cell Line; D019610:Cytoprotection; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D016501:Neurites / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D018620:PrPSc Proteins / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation
chemical_list: D015852:Eukaryotic Initiation Factor-2; D048049:Extracellular Signal-Regulated MAP Kinases; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D018620:PrPSc Proteins; D011328:Prions; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C489791:Stip1 protein, mouse; C546843:mTOR protein, mouse