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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.

This 96-well-plate ‘real-time quaking-induced conversion’ assay allows the detection of abnormal prion protein in human brain and CSF samples. It can be applied to study many protein misfolding diseases, as well as for drug screening and prion strain discrimination. The development and adaption of in vitro misfolded protein amplification systems has been a major innovation in the detection of abnormally folded prion protein scrapie (PrP Sc ) in human brain and cerebrospinal fluid (CSF) samples. Herein, we describe a fast and efficient protein amplification technique, real-time quaking-induced conversion (RT-QuIC), for the detection of a PrP Sc seed in human brain and CSF. In contrast to other in vitro misfolded protein amplification assays—such as protein misfolding cyclic amplification (PMCA)—which are based on sonication, the RT-QuIC technique is based on prion seed–induced misfolding and aggregation of recombinant prion protein substrate, accelerated by alternating cycles of shaking and rest in fluorescence plate readers. A single RT-QuIC assay typically analyzes up to 32 samples in triplicate, using a 96-well-plate format. From sample preparation to analysis of results, the protocol takes ∼87 h to complete. In addition to diagnostics, this technique has substantial generic analytical applications, including drug screening, prion strain discrimination, biohazard screening (e.g., to reduce transmission risk related to prion diseases) and the study of protein misfolding; in addition, it can potentially be used for the investigation of other protein misfolding diseases such as Alzheimer's and Parkinson's disease.

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.

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.

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.

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.

Only a few reports have generated induced pluripotent stem cells from patients with prion diseases, making it important to conduct translational studies using cells derived from individuals with prion protein ( PRNP ) mutations. In this study, we established induced pluripotent stem cells from a patient with a glycosylphosphatidylinositol-anchorless PRNP mutation (Y162X), which leads to abnormal deposits of prion protein in various organs. While no abnormal intracellular prion protein deposits were observed in the neurons differentiated from PRNP Y162X induced pluripotent stem cells, extracellular PrP aggregates secretions were significantly increased, and these cells were significantly more sensitive to oxidative stress compared to control cells. Utilizing this PRNP Y162X iPSC-derived neuron model, we discovered that edaravone reduced the sensitivity of PRNP Y162X cells to oxidative stress. Following this finding, we treated a PRNP Y162X patient with edaravone for two years, which successfully suppressed indicators of disease progression. Our study demonstrates that the pathology of the glycosylphosphatidylinositol-anchorless PRNP mutation is associated with oxidative stress and highlights the potential of induced pluripotent stem cell technology in identifying novel treatments for rare prion diseases.

Prions cause a variety of CNS illnesses, such as Creutzfeldt–Jakob disease. In this British kindred, a prion-associated process was associated with chronic diarrhea and autonomic dysfunction, a finding that extends the known disorders caused by these aberrant proteins. The prion diseases are transmissible, fatal, neurodegenerative disorders that may be inherited or acquired or that may occur spontaneously as sporadic Creutzfeldt–Jakob disease. 1 The transmissible agent, or prion, is thought to comprise misfolded and aggregated forms of the normal cell-surface prion protein. Prion propagation is thought to occur by means of seeded protein polymerization, a process involving the binding and templated misfolding of normal cellular prion protein. Similar processes are increasingly recognized as relevant to other, more common neurodegenerative diseases. In prion and other neurodegenerative disorders, the aggregates of misfolded protein in the central nervous system are highly heterogeneous, occurring . . .