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Frontiers in Public Health 2024Human prion disease (PrD), a group of fatal and transmissible neurodegenerative diseases, consists of Creutzfeldt-Jakob disease (CJD), kuru, fatal familial insomnia...
INTRODUCTION
Human prion disease (PrD), a group of fatal and transmissible neurodegenerative diseases, consists of Creutzfeldt-Jakob disease (CJD), kuru, fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker disease (GSS), and variably protease-sensitive prionopathy (VPSPr). The emergence of bovine spongiform encephalopathy (BSE) in cattle and variant CJD (vCJD) has greatly threatened public health, both in humans and animals. Since the 1990's, dozens of countries and territories have conducted PrD surveillance programs.
METHODS
In this study, the case numbers and alternative trends of different types of PrD globally and in various countries or territories from 1993 to 2020 were collected and analyzed based on the data from the websites of the international and national PrD surveillance programs, as well as from relevant publications.
RESULTS
The total numbers of the reported PrD and sporadic CJD (sCJD) cases in 34 countries with accessible annual case numbers were 27,872 and 24,623, respectively. The top seven countries in PrD cases were the USA ( = 5,156), France ( = 3,276), Germany ( = 3,212), Italy ( = 2,995), China ( = 2,662), the UK ( = 2,521), Spain ( = 1,657), and Canada ( = 1,311). The annual PrD case numbers and mortalities, either globally or in the countries, showed an increased trend in the past 27 years. Genetic PrD cases accounted for 10.83% of all reported PrD cases; however, the trend varied largely among the different countries and territories. There have been 485 iatrogenic CJD (iCJD) cases and 232 vCJD cases reported worldwide.
DISCUSSION
The majority of the countries with PrD surveillance programs were high- and upper-middle-income countries. However, most low- and lower-middle-income countries in the world did not conduct PrD surveillance or even report PrD cases, indicating that the number of human PrD cases worldwide is markedly undervalued. Active international PrD surveillance for both humans and animals is still vital to eliminate the threat of prion disease from a public health perspective.
Topics: Humans; Prion Diseases; Global Health; Creutzfeldt-Jakob Syndrome; Animals; Cattle
PubMed: 38939567
DOI: 10.3389/fpubh.2024.1411489 -
Current Opinion in Cell Biology Jun 2024Membrane remodelling is essential for the trafficking of macromolecules throughout the cell, a process that regulates various aspects of cellular health and pathology.... (Review)
Review
Membrane remodelling is essential for the trafficking of macromolecules throughout the cell, a process that regulates various aspects of cellular health and pathology. Recent studies implicate the role of biomolecular condensates in regulating multiple steps of the membrane trafficking pathway including but not limited to the organization of the trafficking machinery, dynamic remodeling of membranes, spatial and functional regulation, and response to cellular signals. The implicated proteins contain key structural elements, most notably prion-like domains within intrinsically disordered regions that are necessary for biomolecular condensate formation at fusion sites in processes like endocytic assembly, autophagy, organelle biosynthesis and synaptic vesicle fusion. Experimental and theoretical advances in the field continue to demonstrate that protein condensates can perform mechanical work, the implications of which can be extrapolated to diverse areas of membrane biology.
PubMed: 38936257
DOI: 10.1016/j.ceb.2024.102393 -
Science (New York, N.Y.) Jun 2024Prion disease is caused by misfolding of the prion protein (PrP) into pathogenic self-propagating conformations, leading to rapid-onset dementia and death. However,...
Prion disease is caused by misfolding of the prion protein (PrP) into pathogenic self-propagating conformations, leading to rapid-onset dementia and death. However, elimination of endogenous PrP halts prion disease progression. In this study, we describe Coupled Histone tail for Autoinhibition Release of Methyltransferase (CHARM), a compact, enzyme-free epigenetic editor capable of silencing transcription through programmable DNA methylation. Using a histone H3 tail-Dnmt3l fusion, CHARM recruits and activates endogenous DNA methyltransferases, thereby reducing transgene size and cytotoxicity. When delivered to the mouse brain by systemic injection of adeno-associated virus (AAV), -targeted CHARM ablates PrP expression across the brain. Furthermore, we have temporally limited editor expression by implementing a kinetically tuned self-silencing approach. CHARM potentially represents a broadly applicable strategy to suppress pathogenic proteins, including those implicated in other neurodegenerative diseases.
Topics: Animals; Dependovirus; Mice; Brain; Prion Proteins; Gene Silencing; Epigenesis, Genetic; Histones; DNA Methylation; DNA (Cytosine-5-)-Methyltransferases; Prion Diseases; Humans; Transgenes
PubMed: 38935715
DOI: 10.1126/science.ado7082 -
Viruses Jun 2024Porcine hemagglutinating encephalomyelitis virus (PHEV) replicates in the upper respiratory tract and tonsils of pigs. Using an air-liquid interface porcine respiratory...
Transcriptome Analysis in Air-Liquid Interface Porcine Respiratory Epithelial Cell Cultures Reveals That the Betacoronavirus Porcine Encephalomyelitis Hemagglutinating Virus Induces a Robust Interferon Response to Infection.
Porcine hemagglutinating encephalomyelitis virus (PHEV) replicates in the upper respiratory tract and tonsils of pigs. Using an air-liquid interface porcine respiratory epithelial cells (ALI-PRECs) culture system, we demonstrated that PHEV disrupts respiratory epithelia homeostasis by impairing ciliary function and inducing antiviral, pro-inflammatory cytokine, and chemokine responses. This study explores the mechanisms driving early innate immune responses during PHEV infection through host transcriptome analysis. Total RNA was collected from ALI-PRECs at 24, 36, and 48 h post inoculation (hpi). RNA-seq analysis was performed using an Illumina Hiseq 600 to generate 100 bp paired-end reads. Differential gene expression was analyzed using DeSeq2. PHEV replicated actively in ALI-PRECs, causing cytopathic changes and progressive mucociliary disruption. Transcriptome analysis revealed downregulation of cilia-associated genes such as , , , , and , and acidic sialomucin . PHEV also activated antiviral signaling pathways, significantly increasing the expression of interferon-stimulated genes (, , , and ) and chemokine genes ( and ), highlighting inflammatory regulation. This study contributes to elucidating the molecular mechanisms of the innate immune response to PHEV infection of the airway epithelium, emphasizing the critical roles of the mucociliary, interferon, and chemokine responses.
Topics: Animals; Swine; Gene Expression Profiling; Epithelial Cells; Interferons; Betacoronavirus 1; Immunity, Innate; Virus Replication; Coronavirus Infections; Cytokines; Transcriptome; Respiratory Mucosa; Swine Diseases; Cells, Cultured; Deltacoronavirus
PubMed: 38932231
DOI: 10.3390/v16060939 -
Animals : An Open Access Journal From... Jun 2024Prion disorders are fatal infectious diseases that are caused by a buildup of pathogenic prion protein (PrP) in susceptible mammals. According to new findings, the...
First Report of Single Nucleotide Polymorphisms (SNPs) of the Leporine Shadow of Prion Protein Gene () and Absence of Nonsynonymous SNPs in the Open Reading Frame (ORF) in Rabbits.
Prion disorders are fatal infectious diseases that are caused by a buildup of pathogenic prion protein (PrP) in susceptible mammals. According to new findings, the shadow of prion protein (Sho) encoded by the shadow of prion protein gene () is associated with prion protein (PrP), promoting the progression of prion diseases. Although genetic polymorphisms in are associated with susceptibility to several prion diseases, genetic polymorphisms in the rabbit gene have not been investigated in depth. We discovered two novel single nucleotide polymorphisms (SNPs) in the leporine gene on chromosome 18 and found strong linkage disequilibrium (LD) between them. Additionally, strong LD was not found between the polymorphisms of and genes in rabbits. Furthermore, nonsynonymous SNPs that alter the amino acid sequences within the open reading frame (ORF) of have been observed in prion disease-susceptible animals, but this is the first report in rabbits. As far as we are aware, this study represents the first examination of the genetic features of the rabbit gene.
PubMed: 38929426
DOI: 10.3390/ani14121807 -
Preventive Veterinary Medicine Jun 2024Establishing freedom from disease is a key component of surveillance and may have direct consequences for trade and economy. Transboundary populations pose challenges in...
Establishing freedom from disease is a key component of surveillance and may have direct consequences for trade and economy. Transboundary populations pose challenges in terms of variable legislation, efforts, and data availability between countries, often limiting surveillance efficiency. Chronic wasting disease (CWD) is a contagious prion disease of cervids. The long incubation period and slow initial epidemic growth make it notoriously difficult to detect CWD in the early phase of an epidemic. The recent emergence of CWD in wild reindeer in Norway poses a threat to approximately 250,000 semi-domesticated reindeer in Norway and 250,000 in Sweden, including transboundary populations. Here, we provide a first analysis of surveillance data (2016-2022) from all reindeer districts in Norway and Sweden to determine the probability of freedom from CWD infection. During the six years, 6017 semi-domesticated reindeer were tested in Sweden and 51,974 in Norway. Most samples came from healthy slaughtered animals (low risk). Reindeer use large and remote areas and (high risk) samples from fallen stock and animals with clinical signs were difficult to obtain. A scenario tree model was run for seven different set of values for the input parameters (design prevalence within and between districts, probability of introduction, and relative risks) to determine the effect on surveillance sensitivity. At the national level, the mean probability of disease freedom was 59.0 % in Sweden and 87.0 % in Norway by 2021. The most marked effect on sensitivity was varying the design prevalence both within and between districts. Uncertainty about relative risk ratios affected sensitivity for Sweden more than for Norway, due to the higher proportion of animals in the high-risk group in the former (13.8 % vs. 2.1 %, respectively). A probability of disease freedom of 90 % or higher was reached in 8.2 % of the 49 districts in Sweden and 43.5 % of the 46 districts in Norway for a design prevalence of 0.5 %. The probability of freedom remained below 60 % in 29 districts (59.2 %) in Sweden and 10 districts (21.7 %) in Norway. At the national level, only Norway had a sufficiently large number of samples to reach a probability of more than 95 % of disease freedom within a period of 10 years. Our cross-border assessment forms an important knowledge base for designing future surveillance efforts depending on the spatial pattern of prevalence of CWD and risk of spread.
PubMed: 38924869
DOI: 10.1016/j.prevetmed.2024.106242 -
Journal of Neurovirology Jun 2024The cellular prion protein (PrP) is an extracellular cell membrane protein. Due to its diversified roles, a definite role of PrP has been difficult to establish. During...
The cellular prion protein (PrP) is an extracellular cell membrane protein. Due to its diversified roles, a definite role of PrP has been difficult to establish. During viral infection, PrP has been reported to play a pleiotropic role. Here, we have attempted to envision the function of PrP in the neurotropic m-CoV-MHV-RSA59-induced model of neuroinflammation in C57BL/6 mice. A significant upregulation of PrP at protein and mRNA levels was evident in infected mouse brains during the acute phase of neuroinflammation. Furthermore, investigation of the effect of MHV-RSA59 infection on PrP expression in specific neuronal, microglial, and astrocytoma cell lines, revealed a differential expression of prion protein during neuroinflammation. Additionally, siRNA-mediated downregulation of prnp transcripts reduced the expression of viral antigen and viral infectivity in these cell lines. Cumulatively, our results suggest that PrP expression significantly increases during acute MHV-RSA59 infection and that PrP also assists in viral infectivity and viral replication.
PubMed: 38922550
DOI: 10.1007/s13365-024-01215-w -
Pathogens (Basel, Switzerland) May 2024Prion diseases such as scrapie, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) affect domesticated and wild herbivorous mammals. Animals...
Prion diseases such as scrapie, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) affect domesticated and wild herbivorous mammals. Animals afflicted with CWD, the transmissible spongiform encephalopathy of cervids (deer, elk, and moose), shed prions into the environment, where they may persist and remain infectious for years. These environmental prions may remain in soil, be transported in surface waters, or assimilated into plants. Environmental sampling is an emerging area of TSE research and can provide more information about prion fate and transport once shed by infected animals. In this study, we have developed the first published method for the extraction and detection of prions in plant tissue using the real-time quaking-induced conversion (RT-QuIC) assay. Incubation with a zwitterionic surfactant followed by precipitation with sodium phosphotungstate concentrates the prions within samples and allows for sensitive detection of prion seeding activity. Using this protocol, we demonstrate that prions can be detected within plant tissues and on plant surfaces using the RT-QuIC assay.
PubMed: 38921750
DOI: 10.3390/pathogens13060452 -
Cells Jun 2024Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate...
Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7-8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.
Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Mice; Mice, Transgenic; Alzheimer Disease; Cognition; Phosphodiesterase 4 Inhibitors; Microglia; Disease Models, Animal; Presenilin-1; Humans; Amyloid beta-Protein Precursor; Male
PubMed: 38920631
DOI: 10.3390/cells13121000 -
Frontiers in Microbiology 2024Commensal intestinal bacteria shape our microbiome and have decisive roles in preserving host metabolic and immune homeostasis. They conspicuously impact disease...
Longitudinal microbiome investigation throughout prion disease course reveals pre- and symptomatic compositional perturbations linked to short-chain fatty acid metabolism and cognitive impairment in mice.
Commensal intestinal bacteria shape our microbiome and have decisive roles in preserving host metabolic and immune homeostasis. They conspicuously impact disease development and progression, including amyloid-beta (Aβ) and alpha (α)-synuclein pathology in neurodegenerative diseases, conveying the importance of the brain-gut-microbiome axis in such conditions. However, little is known about the longitudinal microbiome landscape and its potential clinical implications in other protein misfolding disorders, such as prion disease. We investigated the microbiome architecture throughout prion disease course in mice. Fecal specimens were assessed by 16S ribosomal RNA sequencing. We report a temporal microbiome signature in prion disease and uncovered alterations in Lachnospiraceae, Ruminococcaceae, Desulfovibrionaceae, and Muribaculaceae family members in this disease. Moreover, we determined the enrichment of Bilophila, a microorganism connected to cognitive impairment, long before the clinical manifestation of disease symptoms. Based on temporal microbial abundances, several associated metabolic pathways and resulting metabolites, including short-chain fatty acids, were linked to the disease. We propose that neuroinflammatory processes relate to perturbations of the intestinal microbiome and metabolic state by an interorgan brain-gut crosstalk. Furthermore, we describe biomarkers possibly suitable for early disease diagnostics and anti-prion therapy monitoring. While our study is confined to prion disease, our discoveries might be of equivalent relevance in other proteinopathies and central nervous system pathologies.
PubMed: 38919500
DOI: 10.3389/fmicb.2024.1412765