Publication Date:
2015-06-11
Description:
Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G--〉V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486072/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486072/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Asante, Emmanuel A -- Smidak, Michelle -- Grimshaw, Andrew -- Houghton, Richard -- Tomlinson, Andrew -- Jeelani, Asif -- Jakubcova, Tatiana -- Hamdan, Shyma -- Richard-Londt, Angela -- Linehan, Jacqueline M -- Brandner, Sebastian -- Alpers, Michael -- Whitfield, Jerome -- Mead, Simon -- Wadsworth, Jonathan D F -- Collinge, John -- MC_U123160653/Medical Research Council/United Kingdom -- Department of Health/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Jun 25;522(7557):478-81. doi: 10.1038/nature14510. Epub 2015 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. ; 1] MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK [2] Papua New Guinea Institute of Medical Research, Goroka, Eastern Highlands Province, Papua New Guinea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26061765" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Amino Acid Substitution/genetics
;
Animals
;
Cattle
;
Creutzfeldt-Jakob Syndrome/genetics/prevention & control
;
Encephalopathy, Bovine Spongiform/genetics
;
Female
;
Heterozygote
;
Homozygote
;
Humans
;
Kuru/epidemiology/genetics/prevention & control
;
Mice
;
Mice, Transgenic
;
Papua New Guinea/epidemiology
;
Polymorphism, Genetic/*genetics
;
PrPSc Proteins/chemistry/genetics/metabolism
;
Prion Diseases/epidemiology/*genetics/*prevention & control/transmission
;
Prions/chemistry/*genetics/*metabolism/pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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