Dimerization of the cellular prion protein inhibits propagation of scrapie prions

Identification: Tatzelt, Jorg


Description

Dimerization of the cellular prion protein inhibits propagation of scrapie prions
 
Anna D. Engelke1*, Anika Gonsberg1*, Simrika Thapa2*, Sebastian Jung1, Sarah Ulbrich1, Hermann M. Schätzl2, Konstanze F. Winklhofer1 and Jorg Tatzelt1#
1Department Biochemistry of Neurodegenerative Diseases, Ruhr University Bochum, Germany; 2Department of Comparative Biology and Experimental Medicine, University of Calgary, Canada
*contributed equally and share first authorship
#corresponding author
      
A central step in the pathogenesis of prion diseases is the conformational transition of the cellular prion protein (PrPC) into the scrapie isoform, denoted PrPSc. Studies in transgenic mice indicated that the conversion requires a direct interaction between PrPC and PrPSc, however, insights in the underlying mechanisms are still missing. Interestingly, only a subfraction of PrPC is converted in scrapie-infected cells, suggesting that not all PrPC species are suitable substrates for the conversion. Based on the observation that PrPC can form homodimers under physiological conditions with the internal hydrophobic domain (HD) serving as a putative dimerization domain, we wondered whether PrP dimerization could be implicated in the formation of neurotoxic and/or infectious PrP conformers. First, we analyzed a possible impact of pathogenic mutations in the HD that induce a spontaneous neurodegenerative disease in transgenic mice. Similarly to wildtype (wt) PrPC the neurotoxic mutant PrP(AV3) formed homodimers as well as heterodimers with wtPrPC. Notably, forced dimerization of PrP via an intermolecular disulfide bond did not interfere with its maturation and intracellular trafficking. Covalently linked PrP dimers were complex glycosylated, GPI-anchored and sorted to the outer leaflet of the plasma membrane. However, dimerization of PrPC completely blocked its conversion into PrPSc in chronically scrapie-infected mouse neuroblastoma cells. Moreover, PrPC dimers had a dominant negative effect on PrPSc propagation in trans. Our study suggests that PrPC monomers are the major substrates for PrPSc propagation and reveals the possibility to halt prion formation by stabilizing PrPC dimers.
 
Funding: This work was supported by the Deutsche Forschungsgemeinschaft (TA167/6)
 

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