title: Expression of the Prion Protein Family Member Shadoo Causes Drug Hypersensitivity That Is Diminished by the Coexpression of the Wild Type Prion Protein.
abstract: The prion protein (PrP) seems to exert both neuroprotective and neurotoxic activities. The toxic activities are associated with the C-terminal globular parts in the absence of the flexible N terminus, specifically the hydrophobic domain (HD) or the central region (CR). The wild type prion protein (PrP-WT), having an intact flexible part, exhibits neuroprotective qualities by virtue of diminishing many of the cytotoxic effects of these mutant prion proteins (PrPΔHD and PrPΔCR) when coexpressed. The prion protein family member Doppel, which possesses a three-dimensional fold similar to the C-terminal part of PrP, is also harmful to neuronal and other cells in various models, a phenotype that can also be eliminated by the coexpression of PrP-WT. In contrast, another prion protein family member, Shadoo (Sho), a natively disordered protein possessing structural features similar to the flexible N-terminal tail of PrP, exhibits PrP-WT-like protective properties. Here, we report that, contrary to expectations, Sho expression in SH-SY5Y or HEK293 cells induces the same toxic phenotype of drug hypersensitivity as PrPΔCR. This effect is exhibited in a dose-dependent manner and is also counteracted by the coexpression of PrP-WT. The opposing effects of Shadoo in different model systems revealed here may be explored to help discern the relationship of the various toxic activities of mutant PrPs with each other and the neurotoxic effects seen in neurodegenerative diseases, such as transmissible spongiform encephalopathy and Alzheimer disease.
authors.affiliation: From the Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, H-6726 Szeged, Hungary.
authors.forename: Antal
authors.initials: A
authors.lastname: Nyeste
authors.affiliation: the Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary, and.
authors.forename: Petra
authors.initials: P
authors.lastname: Bencsura
authors.affiliation: the Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary, and the Institute of Chemistry, Eötvös Loránd University, H-1117 Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Vida
authors.affiliation: the Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary, and.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Hegyi
authors.affiliation: the Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary, and.
authors.forename: László
authors.initials: L
authors.lastname: Homolya
authors.affiliation: From the Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, H-6726 Szeged, Hungary.
authors.forename: Elfrieda
authors.initials: E
authors.lastname: Fodor
authors.affiliation: From the Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, H-6726 Szeged, Hungary, the Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary, and welker.ervin@brc.mta.hu.
authors.forename: Ervin
authors.initials: E
authors.lastname: Welker
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D058851:GPI-Linked Proteins; D017353:Gene Deletion; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072002:Prion Proteins; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D058851:GPI-Linked Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D011994:Recombinant Proteins; C523856:Sprn protein, mouse
keywords: Shadoo; cell death; cell surface protein; drug resistance; lentivirus; neuroblastoma; prion; prion disease; transposable element (TE); zeocin