Phospholipid cofactor solubilization inhibits formation of native prions

The propagation of infectious mammalian prions in vitro requires cofactors, such as phospholipid or RNA molecules. Here, we report that the ability of phospholipids to act as prion cofactors for the conversion of GPI-anchored native prion protein substrate (PrPC) into its infectious conformation (PrPSc) is inhibited by phospholipid solubilization. These results suggest that bilayer membrane architecture may play an important role in prion formation. AbstractCofactor molecules are required to generate infectious mammalian prions in vitro. Mouse and hamster prions appear to have different cofactor preferences: Whereas both mouse and hamster prions can use phosphatidylethanolamine (PE) as a prion cofactor, only hamster prions can also use single-stranded RNA as an alternative cofactor. Here, we investigated the effect of detergent solubilization on rodent prion formation in vitro. We discovered that detergents that can solubilize PE (n-octylglucoside, n-octylgalactoside, and CHAPS) inhibit mouse prion formation in serial protein misfolding cyclic amplification (sPMCA) reactions using bank vole brain homogenate substrate, whereas detergents that are unable to solubilize PE (Triton X-100 and IPEGAL) have no effect. For all three PE-solubilizing detergents, inhibition of RML mouse prion formation was only observed above the critical micellar concentration (CMC). Two other mouse prion strains, Me7 and 301C, were also inhibited by the three PE-solubilizing detergents but not by Trito...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research