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This study looks at a polymorphism of the human prion protein gene, which results in a G-to-V substitution at residue 127, in transgenic mice expressing different human prion proteins, finding that mice heterozygous for the G127V polymorphism are resistant to both kuru and classical CJD prions, but there is some transmission of variant CJD prions; most remarkable, however, is that mice homozygous for V127 are completely resistant to all prion strains. Disease-resistant human prion protein Long-term studies in Papua New Guinea, where the prion disease kuru has been endemic, identified a polymorphism of the human prion protein (PrP) gene — a glycine to valine substitution at residue 127 — that provided a high degree of protection from kuru and was positively selected for during the kuru epidemic. Here John Collinge and colleagues study this G127V polymorphism in detail in transgenic mice expressing different human prion proteins. Mice heterozygous for the G127V polymorphism, which mirrors the human genotype found in Papua New Guinea, are resistant to both kuru and classical Creutzfeldt–Jakob disease (CJD) prions, but there was some transmission of variant CJD, a bovine spongiform encephalopathy (BSE)-derived strain that the humans in Papua New Guinea were never exposed to. Most remarkably, however, mice homozygous for 127V were completely resistant to all prion strains. This represents a previously unknown mechanism of protection against prions; the more common polymorphism M129V is protective only in the heterozygous state. How a single amino acid change can offer such protection awaits further studies. Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP) 1 . 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 2 . 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.

The prion paradigm – the hypothesis that the seeded aggregation of certain proteins is key to understanding age-related neurodegenerative disorders – is evaluated in relation to recent studies and disease models; the paradigm suggests a unifying pathogenic principle with broad relevance to a large class of currently intractable diseases. Pathophysiology of prion infections and age-linked neurodegeneration There is growing speculation that the pathophysiological features common to age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, and prion infections, such as Creutzfeldt–Jakob disease, may be key to our understanding of these conditions. In this Review, Mathias Jucker and Lary Walker consider recent work on the parallels between the self-propagating and misfolding protein aggregates associated with neurodegeneration and the infectious and self-seeding activities of prions. They conclude that the 'prion paradigm' linking these two groups of diseases could lead to a better understanding of the pathology and possible approaches to therapy for diseases that have so far proved intractable. For several decades scientists have speculated that the key to understanding age-related neurodegenerative disorders may be found in the unusual biology of the prion diseases. Recently, owing largely to the advent of new disease models, this hypothesis has gained experimental momentum. In a remarkable variety of diseases, specific proteins have been found to misfold and aggregate into seeds that structurally corrupt like proteins, causing them to aggregate and form pathogenic assemblies ranging from small oligomers to large masses of amyloid. Proteinaceous seeds can therefore serve as self-propagating agents for the instigation and progression of disease. Alzheimer’s disease and other cerebral proteopathies seem to arise from the de novo misfolding and sustained corruption of endogenous proteins, whereas prion diseases can also be infectious in origin. However, the outcome in all cases is the functional compromise of the nervous system, because the aggregated proteins gain a toxic function and/or lose their normal function. As a unifying pathogenic principle, the prion paradigm suggests broadly relevant therapeutic directions for a large class of currently intractable diseases.

Key Points Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of humans and many animal species that are caused by prions. The main constituent of prions is scrapie prion protein (PrP Sc ), an aggregated moiety of the host-derived membrane glycolipoprotein cellular prion protein (PrP C ). Although PrP C is encoded by the host genome, prions were found to encipher many phenotypic TSE variants, known as prion strains. Prion strains are TSE isolates that, when inoculated into new hosts, consistently cause disease with specific characteristics, such as incubation period, patterns of PrP Sc distribution and relative severity of spongiform changes in the brain (the lesion profile).The agent-specified information of prion strains is thought to be contained within distinct conformations of various PrP Sc isotypes. Prions exert their destructive effects predominantly, if not exclusively, within the central nervous system. However, the direct cause of neurotoxicity remains unclear. PrP C is required for prion replication because mice that lack PrP C are resistant to prions. The presence of PrP C on neurons is a prerequisite for prion-induced neurotoxicity. A series of transgenic mice that express various prion protein mutants indicate that deletion of specific regions of PrP C can render it neurotoxic. This toxicity is modulated by co-expression of wild-type PrP C . Currently, there is no reagent allowing non-invasive, pre-mortem diagnosis of prion diseases. In view of recent unfortunate cases of Creutzfeldt–Jakob disease infection through blood transfusion, reliable, specific and, most importantly, sensitive reagents are urgently needed. Although it is now accepted that the infectious agent that causes transmissible spongiform encephalopathies is PrP Sc , recent insights into the existence of prion strains pose a fascinating challenge to prion research. What is the nature of prion strains? And how can they be discriminated? Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that are caused by prions and affect humans and many animal species. It is now widely accepted that the infectious agent that causes TSEs is PrP Sc , an aggregated moiety of the host-derived membrane glycolipoprotein PrP C . Although PrP C is encoded by the host genome, prions themselves encipher many phenotypic TSE variants, known as prion strains. Prion strains are TSE isolates that, after inoculation into distinct hosts, cause disease with consistent characteristics, such as incubation period, distinct patterns of PrP Sc distribution and spongiosis and relative severity of the spongiform changes in the brain. The existence of such strains poses a fascinating challenge to prion research.

Most cases of human prion disease arise due to spontaneous misfolding of WT or mutant prion protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether spontaneous prion generation can occur within the mouse lifespan in the absence of protein overexpression and how disease-causing mutations affect prion strain properties. To address these issues, we generated knockin mice that express the misfolding-prone bank vole prion protein (BVPrP). While mice expressing WT BVPrP (I109 variant) remained free from neurological disease, a subset of mice expressing BVPrP with mutations (D178N or E200K) causing genetic prion disease developed progressive neurological illness. Brains from spontaneously ill knockin mice contained prion disease-specific neuropathological changes as well as atypical protease-resistant BVPrP. Moreover, brain extracts from spontaneously ill D178N- or E200K-mutant BVPrP-knockin mice exhibited prion seeding activity and transmitted disease to mice expressing WT BVPrP. Surprisingly, the properties of the D178N- and E200K-mutant prions appeared identical before and after transmission, suggesting that both mutations guide the formation of a similar atypical prion strain. These findings imply that knockin mice expressing mutant BVPrP spontaneously develop a bona fide prion disease and that mutations causing prion diseases may share a uniform initial mechanism of action.

Mammalian prions are lethal transmissible pathogens that cause fatal neurodegenerative diseases in humans and animals. They consist of fibrils of misfolded, host-encoded prion protein (PrP) which propagate through templated protein polymerisation. Prion strains produce distinct clinicopathological phenotypes in the same host and appear to be encoded by distinct misfolded PrP conformations and assembly states. Despite fundamental advances in our understanding of prion biology, key knowledge gaps remain. These include precise delineation of prion replication mechanisms, detailed explanation of the molecular basis of prion strains and inter-species transmission barriers, and the structural definition of neurotoxic PrP species. Central to addressing these questions is the determination of prion structure. While high-resolution definition of ex vivo prion fibrils once seemed unlikely, recent advances in cryo-electron microscopy (cryo-EM) and computational methods for 3D reconstruction of amyloids have now made this possible. Recently, near-atomic resolution structures of highly infectious, ex vivo prion fibrils from hamster 263K and mouse RML prion strains were reported. The fibrils have a comparable parallel in-register intermolecular β-sheet (PIRIBS) architecture that now provides a structural foundation for understanding prion strain diversity in mammals. Here, we review these new findings and discuss directions for future research.

Prion disease is a neurodegenerative malady, which is believed to be transmitted via a prion protein in its abnormal conformation (PrP Sc ). Previous studies have failed to demonstrate that prion disease could be induced in wild-type animals using recombinant prion protein (rPrP) produced in Escherichia coli . Here, we report that prion infectivity was generated in Syrian hamsters after inoculating full-length rPrP that had been converted into the cross-β-sheet amyloid form and subjected to annealing. Serial transmission gave rise to a disease phenotype with highly unique clinical and neuropathological features. Among them were the deposition of large PrP Sc plaques in subpial and subependymal areas in brain and spinal cord, very minor lesioning of the hippocampus and cerebellum, and a very slow progression of disease after onset of clinical signs despite the accumulation of large amounts of PrP Sc in the brain. The length of the clinical duration is more typical of human and large animal prion diseases, than those of rodents. Our studies establish that transmissible prion disease can be induced in wild-type animals by inoculation of rPrP and introduce a valuable new model of prion diseases.

Prion diseases are progressive, incurable and fatal neurodegenerative conditions. The term ‘prion’ was first nominated to express the revolutionary concept that a protein could be infectious. We now know that prions consist of PrPSc, the pathological aggregated form of the cellular prion protein PrPC. Over the years, the term has been semantically broadened to describe aggregates irrespective of their infectivity, and the prion concept is now being applied, perhaps overenthusiastically, to all neurodegenerative diseases that involve protein aggregation. Indeed, recent studies suggest that prion diseases (PrDs) and protein misfolding disorders (PMDs) share some common disease mechanisms, which could have implications for potential treatments. Nevertheless, the transmissibility of bona fide prions is unique, and PrDs should be considered as distinct from other PMDs.

Prion diseases are invariably fatal neurodegenerative diseases that affect some mammalian species, including humans. These diseases are caused by the misfolding of the cellular prion protein (PrP C ) into a pathologic isoform (PrP Sc ). The prion protein is highly conserved across mammals. However, some species present lower susceptibility to prion diseases than others. This behavior is likely explained by the resistance of these animal species’ prion proteins to acquire a pathological conformation. Therefore, the tertiary structure and interspecific variations encoded in the primary structure determine a PrP proneness to misfolding. For this reason, we studied the PRNP gene from a phylogenetic perspective, potentially unveiling evolutionary events related to prion diseases. We generated a database of mammalian PRNP sequences and constructed phylogenetic trees based on nucleotide sequence variations. We aligned 1146 PRNP gene sequences from 901 different mammalian species and built a PRNP gene-based phylogenetic tree. Classical phylogenetic orders tend to maintain their clustering in the PRNP gene tree. Nonetheless, the few differences found may shed some light on potential evolutionary constraints posed by prion disorders. Moreover, this phylogenetic study was combined with an in vitro misfolding study. Protein Misfolding Shaking Amplification (PMSA) was used to evaluate the tendency of many of these proteins to misfold. This comprehensive analysis spanned a wide range of mammalian prion protein sequences and included analysis of different variants with a focus on the human rs1799990 locus (c.385A > G, p.Met129Val). This variant, widely linked to prion disease susceptibility in humans, is explored in the context of its evolutionary origins. All in all, our PRNP gene-based tree, despite showing some topological differences with the reference species tree that could be in some cases related to prion disease susceptibility, is not significantly distinct. Indicating that the proneness of a PrP variant to misfold spontaneously has not shaped the evolution of this gene.

Prion diseases (PrD) or transmissible spongiform encephalopathies (TSE) are invariably fatal and pathogenic neurodegenerative disorders caused by the self-propagated misfolding of cellular prion protein (PrP C ) to the neurotoxic pathogenic form (PrP TSE ) via a yet undefined but profoundly complex mechanism. Despite several decades of research on PrD, the basic understanding of where and how PrP C is transformed to the misfolded, aggregation-prone and pathogenic PrP TSE remains elusive. The primary clinical hallmarks of PrD include vacuolation-associated spongiform changes and PrP TSE accumulation in neural tissue together with astrogliosis. The difficulty in unravelling the disease mechanisms has been related to the rare occurrence and long incubation period (over decades) followed by a very short clinical phase (few months). Additional challenge in unravelling the disease is implicated to the unique nature of the agent, its complexity and strain diversity, resulting in the heterogeneity of the clinical manifestations and potentially diverse disease mechanisms. Recent advances in tissue isolation and processing techniques have identified novel means of intercellular communication through extracellular vesicles (EVs) that contribute to PrP TSE transmission in PrD. This review will comprehensively discuss PrP TSE transmission and neurotoxicity, focusing on the role of EVs in disease progression, biomarker discovery and potential therapeutic agents for the treatment of PrD.