Document Detail


Isolation of phosphatidylethanolamine as a solitary cofactor for prion formation in the absence of nucleic acids.
MedLine Citation:
PMID:  22586108     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Infectious prions containing the pathogenic conformer of the mammalian prion protein (PrP(Sc)) can be produced de novo from a mixture of the normal conformer (PrP(C)) with RNA and lipid molecules. Recent reconstitution studies indicate that nucleic acids are not required for the propagation of mouse prions in vitro, suggesting the existence of an alternative prion propagation cofactor in brain tissue. However, the identity and functional properties of this unique cofactor are unknown. Here, we show by purification and reconstitution that the molecule responsible for the nuclease-resistant cofactor activity in brain is endogenous phosphatidylethanolamine (PE). Synthetic PE alone facilitates conversion of purified recombinant (rec)PrP substrate into infectious recPrP(Sc) molecules. Other phospholipids, including phosphatidylcholine, phosphatidylserine, phosphatidylinositol, and phosphatidylglycerol, were unable to facilitate recPrP(Sc) formation in the absence of RNA. PE facilitated the propagation of PrP(Sc) molecules derived from all four different animal species tested including mouse, suggesting that unlike RNA, PE is a promiscuous cofactor for PrP(Sc) formation in vitro. Phospholipase treatment abolished the ability of brain homogenate to reconstitute the propagation of both mouse and hamster PrP(Sc) molecules. Our results identify a single endogenous cofactor able to facilitate the formation of prions from multiple species in the absence of nucleic acids or other polyanions.
Authors:
Nathan R Deleault; Justin R Piro; Daniel J Walsh; Fei Wang; Jiyan Ma; James C Geoghegan; Surachai Supattapone
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-05-14
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-30     Completed Date:  2012-08-24     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8546-51     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Brain / metabolism*,  pathology
Cricetinae
Immunohistochemistry
Mice
Nucleic Acids / metabolism*
Phosphatidylcholines / metabolism
Phosphatidylethanolamines / metabolism*
Phosphatidylglycerols / metabolism
Phosphatidylinositols / metabolism
Phosphatidylserines / metabolism
Prions / chemistry,  genetics,  metabolism*
Protein Folding
RNA / metabolism
Recombinant Proteins / metabolism
Grant Support
ID/Acronym/Agency:
2R01 NS046478/NS/NINDS NIH HHS; R01 NS055875/NS/NINDS NIH HHS; R01 NS060729/NS/NINDS NIH HHS; R01 NS071035/NS/NINDS NIH HHS; R01 NS071035/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Nucleic Acids; 0/Phosphatidylcholines; 0/Phosphatidylethanolamines; 0/Phosphatidylglycerols; 0/Phosphatidylinositols; 0/Phosphatidylserines; 0/Prions; 0/Recombinant Proteins; 39382-08-6/phosphatidylethanolamine; 63231-63-0/RNA
Comments/Corrections

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