title: A naturally occurring variant of the human prion protein completely prevents prion disease.
abstract: 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.
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Asante
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Smidak
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Grimshaw
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Houghton
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tomlinson
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Asif
authors.initials: A
authors.lastname: Jeelani
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Jakubcova
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Shyma
authors.initials: S
authors.lastname: Hamdan
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Richard-Londt
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Linehan
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Alpers
authors.affiliation: 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.
authors.forename: Jerome
authors.initials: J
authors.lastname: Whitfield
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Jonathan D F
authors.initials: JD
authors.lastname: Wadsworth
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002417:Cattle; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000517:prevention & control; D016643:Encephalopathy, Bovine Spongiform / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007729:Kuru / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D010219:Papua New Guinea / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000235:genetics*; D018620:PrPSc Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control* / Q000635:transmission; D011328:Prions / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018620:PrPSc Proteins; D011328:Prions