Prion最新文献

Chronic wasting disease (CWD) is a highly contagious prion disease occurring in free-ranging and farmed cervids. In the Republic of Korea, cases of CWD continue to be detected almost annually, on both new and occasionally previously infected farms. CWD-infected animals contaminate soil and other environmental components by shedding prions through their excreta. Since shed prions remain infectious for years in the environment, they can act as infectivity reservoirs facilitating horizontal transmission of CWD. To prevent the further spread of CWD and allow farms to resume operations, control measures on infected farms, including topsoil removal and thorough environmental treatment with 2N NaOH, have been implemented in the Republic of Korea. Restocking remediated farms with cervids was permitted after confirming the absence of prion seeding activity in soil samples using protein misfolding cyclic amplification (PMCA). A total of 215 samples from 18 remediated farms were collected and analysed using PMCA, with only 3 samples from 3 farms displaying prion seeding activity. While the disease control measures effectively eliminated prion seeding activity in CWD-affected farms, CWD recurred at two of the 18 remediated farms 4 to 5 years after restocking animals. It remains unclear whether the recurrence of CWD at the two farms was due to residual prions in the environment after the control measures, or the introduction of the infected animals from other farms. This uncertainty is heightened by the annual occurrence of CWD at multiple farms and the absence of a traceability system for farmed cervids.

Bovine Spongiform Encephalopathy (BSE) is a fatal neurodegenerative disease in cattle which can be either classical BSE (C-BSE) or atypical BSE (including H-BSE and L-BSE). Here, we report the results of our analyses of an H-BSE case found in Canada in 2021, indicating restriction of the pathological agent (PrP^Sc) mainly to the central nervous system with no or occasional weak involvement of peripheral tissues. Importantly, a non-synonymous mutation at codon 211 of the PRNP gene was detected and confirmed to be present as a germline mutation. This is the first case of BSE in Canada with a predisposing E211K mutation.

Background: The prion diseases (PrD) are a group of progressive, fatal, neurodegenerative diseases, for which the Medical Research Council Prion Disease Rating Scale (MRC Scale) can be used to assess patients' functional deterioration. Findings from previous qualitative interviews with caregivers and clinical experts identified potential ambiguities in the scale that could lead to inconsistent scoring within and/or between raters.

Methods: A draft User Guide was developed based on findings from a previous qualitative study. The draft included clarifications regarding domain wording, scoring levels, and guidance for response option selection. Five clinical experts with PrD management experience provided written feedback on the draft User Guide, which was incorporated into a revised User Guide. A 90-minute consensus meeting was then held with these experts to confirm the final content to be included in the User Guide.

Results: The final User Guide was designed to accompany the MRC Scale and assist with rater decisions related to which response option most accurately describes a patient's health status. Conclusions: The User Guide is expected to be a valuable complement to the MRC Scale, which is poised to rise in use and prominence as global clinical research efforts accelerate to address the significant unmet need of PrD patients.

The Prion 2024 annual conference, held in Nanchang, China, from 23 to 27 October, drew nearly 300 leading scientists, clinicians, researchers, and students from 17 countries to examine the latest advancements in prion research and related diseases. This landmark event marked the inaugural international prion conference hosted in a developing nation for the first time and celebrated the 20th anniversary of the NeuroPrion Association, the organizing body of this prestigious annual gathering - 'Celebrating Two Decades of Progress: Pioneering a New Era.' The conference spotlighted key themes such as epidemiology, pathogenesis, the connections between ageing and neurodegenerative diseases. It showcased innovative diagnostic and therapeutic strategies for both human and animal prion diseases, as well as related conditions including Alzheimer's and Parkinson's diseases, prion protein-associated cancers, and renal injury. The programme featured 70 invited talks and 21 selected oral presentations, culminating in 7 plenary sessions led by esteemed speakers, including Nobel Laureate Stanley B. Prusiner. This overview summarizes key presentations and highlights significant aspects of the conference, emphasizing the impactful discussions and collaborations that emerged from this historic event.

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders that result from abnormally folded prion proteins. These disorders can be sporadic, acquired, or genetic. Acquired TSEs can be found in a number of animal species including sheep (scrapie), cows (bovine spongiform encephalopathy), and cervids (chronic wasting disease). Chronic wasting disease (CWD) is unusual in that it is found in free ranging animals in their natural environment. There has been heretofore no reported cases of CWD being transmitted to humans; however, the possibility of future adaption for human transmission exists. Several novel approaches for the prevention and treatment of prion disease in humans are under development, including knockdown of endogenous prion expression or overexpression of dominant negative prion forms. Here, I propose that CWD, as a naturally occurring prion disease, should be considered an important testing target for such therapies, which can demonstrate efficacy outside of controlled laboratory environments. Further, from the ethical standpoint of reducing animal suffering, decreasing the CWD burden in cervid populations is highly desirable. Finally, lowering CWD incidence can reduce future possibilities of transmission to humans or to other animal species.

Gerstmann - Sträussler - Scheinker disease (GSS) is a hereditary prion disease characterized by clinicopathological heterogeneity. In Japan, the most common mutation is P102L, typically associated with prion protein (PrP) plaques, spongiform changes, and synaptic PrP deposits. Two major protease-resistant PrP (PrP^res) types occur: type-1 PrP^res (21 kDa) and 8-kDa PrP^res. The PRNP codon 129 polymorphism (methionine or valine) influences disease phenotype, but factors underlying exclusive 8-kDa PrP^res expression remain unclear. We analysed two sibling P102L GSS cases exclusively exhibiting 8-kDa PrP^res (Case 1: 129 MM, haplotype: P102L-129 M, treated with pentosan polysulfate; Case 2: 129 MV, haplotype: P102L-129 M, treated with quinacrine hydrochloride and quinine hydrochloride) and four P102L-129 MM GSS cases exhibiting type-1 and 8-kDa PrP^res (Cases 3-6) to elucidate the clinicopathological effect of 8-kDa PrP^res and PRNP codon 129 polymorphisms. Case 1 predominantly exhibited amyloidogenic PrP plaques; Case 2 exhibited non-amyloidogenic cotton-wool PrP plaques, with minimal synaptic PrP deposits. Despite prolonged survival ( > 20 years), spongiform degeneration and neuronal loss were mild. Cases 3-6 showed numerous amyloidogenic PrP plaques, moderate-to-severe synaptic PrP deposits, and significant tissue damage. Homoeostatic microglial markers were preserved in Cases 1 and 2 but absent in Cases 3-6. Cotton-wool PrP plaques lacked amyloid cores and were associated with 8-kDa PrP^res and codon 129 V from the normal allele. Tissue damage was mild in P102L GSS cases exhibiting 8-kDa PrP^res, suggesting lower pathogenicity. Cotton-wool PrP plaque formation likely involves 8-kDa PrP^res and codon 129 V. Further large-scale studies are warranted to elucidate these mechanisms.

Chronic Wasting Disease (CWD) research has experienced significant growth, spanning diverse disciplines such as genetics, immunology, modelling, and behaviour. To gain a broad understanding of the changes in CWD research focusing cervids, we analysed temporal trends in study location, species, genus investigated, infection types, and population type since the discovery of CWD in 1980s. Our findings indicate that Colorado, USA, published the highest number of articles, followed by Wisconsin, and publication numbers correlated with reported CWD cases in states/provinces. Odocoileus emerged as the most studied genus. Wild populations are studied more commonly than captive populations. Keyword analysis of transmission types shows the discovery of novel transmission modes in the recent past. We also used a novel approach to categorize studies into five themes: field-based, lab-based, math/analytics/modelling-based, management-based, and human dimensions. Overall, most studies captured had a lab-based component. The interdisciplinary or transdisciplinary nature of major disciplines and evolving trends in keywords, particularly the increased reliance on genetics/genomics, accentuate the beginning of using genomics to under and tackle CWD at a fundamental scale. Encapsulated in our analysis, these dynamic changes offer valuable insights for navigating CWD through scientifically informed proactive management decisions in conjunction with existing surveillance efforts not only for the commonly studied species but also for potentially susceptible species.

The FXR1 protein regulates the stability and translation of a number of RNA molecules and plays an important role in the regulation of cellular processes under normal conditions and stress. In particular, this protein is known to be a negative regulator of the key proinflammatory cytokine TNF alpha. We had previously shown that FXR1 functioned in the amyloid form in neurons of the brain of jawed vertebrates. Under stress conditions, FXR1 is incorporated into stress granules in some cell lines, but such studies have not been conducted for neuronal cells. Here, we showed the ability of the FXR1 protein to form cytoplasmic granules in a neuroblastoma cell line under various types of stress. This protein colocalizes with core proteins of neuronal stress granules upon heat shock and sodium arsenite treatment. We also showed that FXR1 colocalizes with anti-amyloid antibodies OC under both normal and stress conditions. Given that stress granules are dynamic structures, we propose that amyloid FXR1-containing RNP particles interact with other stress granule proteins through weak intermolecular hydrogen bonds. Using a yeast model system, we found that FXR1 colocalizes and physically interacts with stress granule proteins such as TIA-1, FMRP, FXR2, and SFPQ. Overall, our results provide new insights into the role of the RNA-binding protein FXR1 in neuronal stress response. We believe that FXR1 inactivation in neuronal stress granules can contribute to an increase in the level of the proinflammatory cytokine TNF alpha in neurodegenerative diseases.

An early diagnosis is required for intervention in prion disease cases. To elucidate the specificity of early electroencephalography discharges in cases of sporadic Creutzfeldt-Jakob disease, we analysed epileptiform discharges through electroencephalography. Nine patients with methionine/methionine type 1/classic sporadic Creutzfeldt-Jakob disease and 20 patients with status epilepticus were included. Generalized periodic discharges, lateralized periodic discharges, and central sagittal sporadic epileptiform discharges were evaluated. Central sagittal sporadic epileptiform discharges were defined as nonrhythmic and nonperiodic waveforms showing generalized spike-and-wave complexes and/or sharp waves predominantly in the central sagittal region. In the sporadic Creutzfeldt-Jakob disease group, central sagittal sporadic epileptiform discharges, lateralized periodic discharges, and generalized periodic discharges were observed in five (55.6%), one (11.1%), and eight (88.9%) patients, respectively, with an average duration from onset to the appearance of the discharges of 1.6, 1.0, and 2.44 months, respectively. In the status epilepticus group, these discharges were detected in one (5.0%), six (30.0%), and six (30.0%) patients, respectively. The incorporation of central sagittal sporadic epileptiform discharges and lateralized periodic discharges into the World Health Organization diagnostic criteria, alongside generalized periodic discharges, significantly shortened the average lapse from symptom onset to sporadic Creutzfeldt-Jakob disease diagnosis (2.06 months vs. 2.44 months; p = 0.02). Central sagittal sporadic epileptiform discharges emerge as promising biomarkers for distinguishing sporadic Creutzfeldt-Jakob disease from status epilepticus, and together with lateralized periodic discharges provide an opportunity for early diagnosis of sporadic Creutzfeldt-Jakob disease.

Chronic wasting disease (CWD) is a fatal, neurodegenerative disease of cervids, and its management heavily relies on diagnostic testing. Test results are commonly used to calculate 'apparent prevalence' (AP) - the percent of animals tested for CWD (CWD tests) with CWD-positive test results (CWD cases) - but this obscures how tests and cases individually contribute to this statistic. This is most relevant when CWD testing is limited because when few animals are tested, detection of even a single infected deer can result in a high AP that poorly reflects reality. We hypothesized that when CWD testing is limited, AP is negatively driven by testing - rather than cases - with more tests corresponding to lower APs. Graphed CWD surveillance data from townships in Illinois and Wisconsin, USA, indicate that CWD AP values ≥50% were only observed when <23 deer were tested. We used Bayesian multilevel zero-inflated Beta regression to model AP as a function of CWD tests, CWD cases and nonlinear transformations of these two terms separately for each state. The best-fit models of both identified a statistically significant negative relationship between AP and testing numbers that was modified by a positive nonlinear test covariate. This means adding tests when testing is low can have a big impact on decreasing the AP, but this relationship weakens as testing increases. We urge treating apparent prevalences ≥50% with caution and emphasize the importance of increasing the test results when initial surveillance has yielded <23 tests.