Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice
| Autor: | Hans A. Kretzschmar, Marko Maringer, Nathalie Daude, Alexander Hepp, David Westaway, Gerda Mitteregger-Kretzschmar, Janina Mielke, Sabina Eigenbrod, Armin Giese, Petra Frick, Vignesh Sakthivelu, Jörg Tatzelt, Uwe Bertsch, Otto Windl, Niklas Piening, Johannes Levin |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Central Nervous System animal diseases lcsh:Medicine Scrapie Biochemistry Nervous System chemistry [Prion Proteins] law.invention Animal Diseases Prion Diseases Mice law chemistry [Histidine] Zoonoses Medicine and Health Sciences Amino Acids lcsh:Science Brain Diseases Multidisciplinary Chemistry Organic Compounds Animal Models Proteases Phenotype Enzymes Animal Prion Diseases Infectious Diseases Experimental Organism Systems Neurology Physical Sciences Recombinant DNA Basic Amino Acids Anatomy Research Article pathology [Scrapie] Gene isoform Genetically modified mouse Transgene Mice Transgenic Mouse Models Research and Analysis Methods Prion Proteins 03 medical and health sciences Model Organisms In vivo Animals Histidine ddc:610 lcsh:R Organic Chemistry Chemical Compounds Biology and Life Sciences Proteins Molecular biology nervous system diseases 030104 developmental biology Enzymology lcsh:Q Zoology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 12, p e0188989 (2017) PLOS ONE 12(12), e0188989 (2017). doi:10.1371/journal.pone.0188989 |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0188989 |
| Popis: | Prion diseases have been linked to impaired copper homeostasis and copper induced-oxidative damage to the brain. Divalent metal ions, such as Cu2+ and Zn2+, bind to cellular prion protein (PrPC) at octapeptide repeat (OR) and non-OR sites within the N-terminal half of the protein but information on the impact of such binding on conversion to the misfolded isoform often derives from studies using either OR and non-OR peptides or bacterially-expressed recombinant PrP. Here we created new transgenic mouse lines expressing PrP with disrupted copper binding sites within all four histidine-containing OR's (sites 1-4, H60G, H68G, H76G, H84G, 'TetraH>G' allele) or at site 5 (composed of residues His-95 and His-110; 'H95G' allele) and monitored the formation of misfolded PrP in vivo. Novel transgenic mice expressing PrP(TetraH>G) at levels comparable to wild-type (wt) controls were susceptible to mouse-adapted scrapie strain RML but showed significantly prolonged incubation times. In contrast, amino acid replacement at residue 95 accelerated disease progression in corresponding PrP(H95G) mice. Neuropathological lesions in terminally ill transgenic mice were similar to scrapie-infected wt controls, but less severe. The pattern of PrPSc deposition, however, was not synaptic as seen in wt animals, but instead dense globular plaque-like accumulations of PrPSc in TgPrP(TetraH>G) mice and diffuse PrPSc deposition in (TgPrP(H95G) mice), were observed throughout all brain sections. We conclude that OR and site 5 histidine substitutions have divergent phenotypic impacts and that cis interactions between the OR region and the site 5 region modulate pathogenic outcomes by affecting the PrP globular domain. |
| Databáze: | OpenAIRE |
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