title: Strain-Dependent Effect of Macroautophagy on Abnormally Folded Prion Protein Degradation in Infected Neuronal Cells.
abstract: Prion diseases are neurodegenerative disorders caused by the accumulation of abnormal prion protein (PrPSc) in the central nervous system. With the aim of elucidating the mechanism underlying the accumulation and degradation of PrPSc, we investigated the role of autophagy in its degradation, using cultured cells stably infected with distinct prion strains. The effects of pharmacological compounds that inhibit or stimulate the cellular signal transduction pathways that mediate autophagy during PrPSc degradation were evaluated. The accumulation of PrPSc in cells persistently infected with the prion strain Fukuoka-1 (FK), derived from a patient with Gerstmann-Sträussler-Scheinker syndrome, was significantly increased in cultures treated with the macroautophagy inhibitor 3-methyladenine (3MA) but substantially reduced in those treated with the macroautophagy inducer rapamycin. The decrease in FK-derived PrPSc levels was mediated, at least in part, by the phosphatidylinositol 3-kinase/MEK signalling pathway. By contrast, neither rapamycin nor 3MA had any apparently effect on PrPSc from either the 22L or the Chandler strain, indicating that the degradation of PrPSc in host cells might be strain-dependent.
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishibashi
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Takujiro
authors.initials: T
authors.lastname: Homma
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Nakagaki
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fuse
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sano
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Hanae
authors.initials: H
authors.lastname: Takatsuki
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Atarashi
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishida
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D059748:Proteolysis; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D018620:PrPSc Proteins; C025946:3-methyladenine; D000225:Adenine; D020123:Sirolimus