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Structural compatibility of infecting prion proteins with those of a new host determine whether they will be successfully transmitted. When the connection was made between bovine spongiform encephalopathy (BSE or “mad cow” disease) and human illnesses in the 1990s, it raised the public profile of the underlying prion diseases as the implications of animal and public health crises, and their economic impacts, became apparent. At the core of these concerns is how prions, the infectious agent, diversify and expand their host range. On page 1154 of this issue, Angers et al. ( 1 ) reveal how this occurs in chronic wasting disease (CWD), a contagious prion disease of wild deer and elk. Its prevalence in the United States raised fears that, like BSE, it might transmit to humans.

Prions are notorious protein-only infectious agents that cause invariably fatal brain diseases following silent incubation periods that can span a lifetime. These diseases can arise spontaneously, through infection or be inherited. Remarkably, prions are composed of self-propagating assemblies of a misfolded cellular protein that encode information, generate neurotoxicity and evolve and adapt in vivo . Although parallels have been drawn with Alzheimer's disease and other neurodegenerative conditions involving the deposition of assemblies of misfolded proteins in the brain, insights are now being provided into the usefulness and limitations of prion analogies and their aetiological and therapeutic relevance.

Mammalian prions propagate as distinct strains and are composed of multichain assemblies of misfolded host-encoded prion protein (PrP). Here, we present a near-atomic resolution cryo-EM structure of PrP fibrils present in highly infectious prion rod preparations isolated from the brains of RML prion-infected mice. We found that prion rods comprise single-protofilament helical amyloid fibrils that coexist with twisted pairs of the same protofilaments. Each rung of the protofilament is formed by a single PrP monomer with the ordered core comprising PrP residues 94–225, which folds to create two asymmetric lobes with the N-linked glycans and the glycosylphosphatidylinositol anchor projecting from the C-terminal lobe. The overall architecture is comparable to that of recently reported PrP fibrils isolated from the brain of hamsters infected with the 263K prion strain. However, there are marked conformational variations that could result from differences in PrP sequence and/or represent distinguishing features of the distinct prion strains. High-resolution structures of mammalian prions have remained elusive. Here, Manka et al. report the cryo-EM structure of infectious RML prion fibrils from mice. Structural similarity with recently reported infectious 263K prion fibrils from hamsters now suggests a common prion architecture.

Alzheimer’s disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aβ as the root cause of AD. We previously reported human transmission of Aβ pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt–Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aβ seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms. Although iatrogenic AD may be rare, and there is no suggestion that Aβ can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aβ assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance. A small number of patients who received growth hormone preparations contaminated with seeds of the amyloid-beta protein developed Alzheimer’s disease many years after treatment.

Recent cryogenic electron microscopy (cryo-EM) studies of infectious, ex vivo, prion fibrils from hamster 263K and mouse RML prion strains revealed a similar, parallel in-register intermolecular β-sheet (PIRIBS) amyloid architecture. Rungs of the fibrils are composed of individual prion protein (PrP) monomers that fold to create distinct N-terminal and C-terminal lobes. However, disparity in the hamster/mouse PrP sequence precludes understanding of how divergent prion strains emerge from an identical PrP substrate. In this study, we determined the near-atomic resolution cryo-EM structure of infectious, ex vivo mouse prion fibrils from the ME7 prion strain and compared this with the RML fibril structure. This structural comparison of two biologically distinct mouse-adapted prion strains suggests defined folding subdomains of PrP rungs and the way in which they are interrelated, providing a structural definition of intra-species prion strain-specific conformations. A near-atomic resolution strain-specific cryo-EM structure of infectious prion fibrils from mice was determined, revealing a structural definition for intra-species prion strain-specific conformations.

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aβ) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)—attributed to the transmission of Aβ seeds—have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.

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.

Neurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plate-immobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aβ aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aβ cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP , and (2) aqueous extracts from brains of individuals who died with Alzheimer’s disease, dementia with Lewy bodies, and Pick’s disease, we demonstrate that Aβ, α-synuclein and tau are toxic to neurons in a manner that requires PrP C . These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.

Two-stage prion infection Prion infections have a clinically silent incubation period that can go on for years or even decades, followed by an aggressive, short clinical phase. Experiments in the RML mouse model of prion disease now show that prion propagation in the brain proceeds by two distinct phases: a relatively brief exponential phase that is not rate-limited by prion protein concentration, followed by a plateau phase. Surprisingly, it is the latter that can be very prolonged, accounting for the majority of the clinically silent incubation period. The similar levels of infectivity at the end of the first and second phase suggest that there is a separation between prion infectivity and toxicity. The authors suggest that the prions are not neurotoxic themselves, but catalyse the formation of such species from host-cell-encoded cellular prion protein. Here it is shown that during the silent phase of prion infection, prions first exponentially propagate until a defined limit is reached. Then a plateau phase follows. Prion propagation is independent of prion concentration, whereas in the plateau phase the time to clinical onset is inversely correlated to prion concentration. The similar levels of infectivity at the end of the first and second phase suggests that there is a separation between prion infectivity and toxicity. Moreover, something seems to limit prion production. It is suggested that the prions are not neurotoxic themselves but catalyse the formation of such species from PrP C . Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity to a toxic pathway. Mammalian prions cause fatal neurodegenerative conditions including Creutzfeldt–Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals 1 . Prion infections are typically associated with remarkably prolonged but highly consistent incubation periods followed by a rapid clinical phase. The relationship between prion propagation, generation of neurotoxic species and clinical onset has remained obscure. Prion incubation periods in experimental animals are known to vary inversely with expression level of cellular prion protein. Here we demonstrate that prion propagation in brain proceeds via two distinct phases: a clinically silent exponential phase not rate-limited by prion protein concentration which rapidly reaches a maximal prion titre, followed by a distinct switch to a plateau phase. The latter determines time to clinical onset in a manner inversely proportional to prion protein concentration. These findings demonstrate an uncoupling of infectivity and toxicity. We suggest that prions themselves are not neurotoxic but catalyse the formation of such species from PrP C . Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity (phase 1) to a toxic (phase 2) pathway.

Sleep disturbance in patients with prion disease is a recognized symptom but the frequency, subtypes of prion disease most commonly affected and the pathogenesis remain unknown. This study identifies the prevalence of sleep disturbance, symptomatology and it’s association with disease subtype, brain MRI changes and codon 129 genotype.Analysis of data collected on clinical symptoms, including sleep disturbance, was conducted in 448 patients with prion disease, recruited to the National Prion Monitoring Cohort. MR brain scans from these patients were examined for the presence of thalamic signal change. Logistic regression analysis was used to determine predictors of sleep disturbance. Sleep disturbance was found to be present in 76% of patients recruited to the NPMC and was present in all subtypes of human prion disease. The most commonly reported symptoms were hypersomnolence (62%), waking at night (53%) and insomnia (43%). Sleep dis- turbance was strongly associated with the presence of depression and there was a significant association found between sleep symptoms and abnormal thalamic signal change identified on MR brain imaging.This study highlights the prevalence of sleep disturbance in patients with prion disease, identifies co-morbid symptoms of depression and finds a significant association between abnormal thalamic signal change and sleep disturbance.