Universität zu Köln

Eigenbrod, Sabina, Frick, Petra, Bertsch, Uwe, Mitteregger-Kretzschmar, Gerda, Mielke, Janina, Maringer, Marko, Piening, Niklas, Hepp, Alexander ORCID: 0000-0003-1288-925X, Daude, Nathalie, Windl, Otto, Levin, Johannes ORCID: 0000-0001-5092-4306, Giese, Armin ORCID: 0000-0002-8238-4102, Sakthivelu, Vignesh, Tatzelt, Joerg, Kretzschmar, Hans and Westaway, David (2017). Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice. PLoS One, 12 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Eigenbrod, Sabina UNSPECIFIED UNSPECIFIED UNSPECIFIED Frick, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertsch, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Mitteregger-Kretzschmar, Gerda UNSPECIFIED UNSPECIFIED UNSPECIFIED Mielke, Janina UNSPECIFIED UNSPECIFIED UNSPECIFIED Maringer, Marko UNSPECIFIED UNSPECIFIED UNSPECIFIED Piening, Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hepp, Alexander UNSPECIFIED orcid.org/0000-0003-1288-925X UNSPECIFIED Daude, Nathalie UNSPECIFIED UNSPECIFIED UNSPECIFIED Windl, Otto UNSPECIFIED UNSPECIFIED UNSPECIFIED Levin, Johannes UNSPECIFIED orcid.org/0000-0001-5092-4306 UNSPECIFIED Giese, Armin UNSPECIFIED orcid.org/0000-0002-8238-4102 UNSPECIFIED Sakthivelu, Vignesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Tatzelt, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Kretzschmar, Hans UNSPECIFIED UNSPECIFIED UNSPECIFIED Westaway, David UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-208043
DOI:	10.1371/journal.pone.0188989
Journal or Publication Title:	PLoS One
Volume:	12
Number:	12
Date:	2017
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELLULAR PRION PROTEIN; CREUTZFELDT-JAKOB-DISEASE; OCTAREPEAT REGION; COPPER-BINDING; FULL-LENGTH; BETA-CLEAVAGE; IN-VITRO; AMINO-TERMINUS; INFECTED MICE; REPEAT REGION Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20804