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1.
BMC Neurol ; 24(1): 92, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468258

RESUMO

BACKGROUND: Human prion diseases (HPDs) are fatal neurodegenerative disorders characterized by abnormal prion proteins (PrPSc). However, the detection of prion seeding activity in patients with high sensitivity remains challenging. Even though real-time quaking-induced conversion (RT-QuIC) assay is suitable for detecting prion seeding activity in a variety of specimens, it shows lower accuracy when whole blood, blood plasma, and blood-contaminated tissue samples are used. In this study, we developed a novel technology for the in vitro amplification of abnormal prion proteins in HPD to the end of enabling their detection with high sensitivity known as the enhanced quaking-induced conversion (eQuIC) assay. METHODS: Three antibodies were used to develop the novel eQUIC method. Thereafter, SD50 seed activity was analyzed using brain tissue samples from patients with prion disease using the conventional RT-QUIC assay and the novel eQUIC assay. In addition, blood samples from six patients with solitary prion disease were analyzed using the novel eQuIC assay. RESULTS: The eQuIC assay, involving the use of three types of human monoclonal antibodies, showed approximately 1000-fold higher sensitivity than the original RT-QuIC assay. However, when this assay was used to analyze blood samples from six patients with sporadic human prion disease, no prion activity was detected. CONCLUSION: The detection of prion seeding activity in blood samples from patients with sporadic prion disease remains challenging. Thus, the development of alternative methods other than RT-QuIC and eQuIC will be necessary for future research.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Príons/metabolismo , Proteínas Priônicas , Doenças Priônicas/diagnóstico , Doenças Priônicas/metabolismo , Encéfalo/metabolismo , Plasma/metabolismo , Síndrome de Creutzfeldt-Jakob/diagnóstico
2.
Front Cell Infect Microbiol ; 14: 1348279, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38435303

RESUMO

Abnormal behavior of α-synuclein and prion proteins is the hallmark of Parkinson's disease (PD) and prion illnesses, respectively, being complex neurological disorders. A primary cause of protein aggregation, brain injury, and cognitive loss in prion illnesses is the misfolding of normal cellular prion proteins (PrPC) into an infectious form (PrPSc). Aggregation of α-synuclein causes disruptions in cellular processes in Parkinson's disease (PD), leading to loss of dopamine-producing neurons and motor symptoms. Alteration in the composition or activity of gut microbes may weaken the intestinal barrier and make it possible for prions to go from the gut to the brain. The gut-brain axis is linked to neuroinflammation; the metabolites produced by the gut microbiota affect the aggregation of α-synuclein, regulate inflammation and immunological responses, and may influence the course of the disease and neurotoxicity of proteins, even if their primary targets are distinct proteins. This thorough analysis explores the complex interactions that exist between the gut microbiota and neurodegenerative illnesses, particularly Parkinson's disease (PD) and prion disorders. The involvement of the gut microbiota, a complex collection of bacteria, archaea, fungi, viruses etc., in various neurological illnesses is becoming increasingly recognized. The gut microbiome influences neuroinflammation, neurotransmitter synthesis, mitochondrial function, and intestinal barrier integrity through the gut-brain axis, which contributes to the development and progression of disease. The review delves into the molecular mechanisms that underlie these relationships, emphasizing the effects of microbial metabolites such as bacterial lipopolysaccharides (LPS), and short-chain fatty acids (SCFAs) in regulating brain functioning. Additionally, it looks at how environmental influences and dietary decisions affect the gut microbiome and whether they could be risk factors for neurodegenerative illnesses. This study concludes by highlighting the critical role that the gut microbiota plays in the development of Parkinson's disease (PD) and prion disease. It also provides a promising direction for future research and possible treatment approaches. People afflicted by these difficult ailments may find hope in new preventive and therapeutic approaches if the role of the gut microbiota in these diseases is better understood.


Assuntos
Microbioma Gastrointestinal , Doença de Parkinson , Príons , Humanos , alfa-Sinucleína , Disbiose , Doenças Neuroinflamatórias , Proteínas Priônicas
3.
Nat Commun ; 15(1): 2112, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459071

RESUMO

Prion diseases are a group of rapidly progressing neurodegenerative disorders caused by the misfolding of the endogenous prion protein (PrPC) into a pathogenic form (PrPSc). This process, despite being the central event underlying these disorders, remains largely unknown at a molecular level, precluding the prediction of new potential outbreaks or interspecies transmission incidents. In this work, we present a method to generate bona fide recombinant prions de novo, allowing a comprehensive analysis of protein misfolding across a wide range of prion proteins from mammalian species. We study more than 380 different prion proteins from mammals and classify them according to their spontaneous misfolding propensity and their conformational variability. This study aims to address fundamental questions in the prion research field such as defining infectivity determinants, interspecies transmission barriers or the structural influence of specific amino acids and provide invaluable information for future diagnosis and therapy applications.


Assuntos
Doenças Priônicas , Príons , Animais , Príons/metabolismo , Proteínas Priônicas/genética , Doenças Priônicas/genética , Doenças Priônicas/metabolismo , Mamíferos/metabolismo , Dobramento de Proteína
4.
Sci Rep ; 14(1): 6294, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491063

RESUMO

Real-time quaking-induced conversion assay (RT-QuIC) exploits templating activity of pathogenic prion protein for ultrasensitive detection of prions. We have utilized second generation RT-QuIC assay to analyze matching post-mortem cerebrospinal fluid and skin samples of 38 prion disease patients and of 30 deceased neurological controls. The analysis of cerebrospinal fluid samples led to 100% sensitivity and 100% specificity, but some samples had to be diluted before the analysis to alleviate the effect of present RT-QuIC inhibitors. The analysis of the corresponding skin samples provided 89.5% sensitivity and 100% specificity. The median seeding dose present in the skin was one order of magnitude higher than in the cerebrospinal fluid, despite the overall fluorescent signal of the skin samples was comparatively lower. Our data support the use of post-mortem cerebrospinal fluid for confirmation of prion disease diagnosis and encourage further studies of the potential of skin biopsy samples for intra-vitam prion diseases´ diagnostics.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Príons/metabolismo , Doenças Priônicas/diagnóstico , Pele/metabolismo , Proteínas Priônicas , Bioensaio , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano
5.
Int J Mol Sci ; 25(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474214

RESUMO

Mood disorders are highly prevalent and heterogenous mental illnesses with devastating rates of mortality and treatment resistance. The molecular basis of those conditions involves complex interplay between genetic and environmental factors. Currently, there are no objective procedures for diagnosis, prognosis and personalization of patients' treatment. There is an urgent need to search for novel molecular targets for biomarkers in mood disorders. Cellular prion protein (PrPc) is infamous for its potential to convert its insoluble form, leading to neurodegeneration in Creutzfeldt-Jacob disease. Meanwhile, in its physiological state, PrPc presents neuroprotective features and regulates neurotransmission and synaptic plasticity. The aim of this study is to integrate the available knowledge about molecular mechanisms underlying the impact of PrPc on the pathophysiology of mood disorders. Our review indicates an important role of this protein in regulation of cognitive functions, emotions, sleep and biological rhythms, and its deficiency results in depressive-like behavior and cognitive impairment. PrPc plays a neuroprotective role against excitotoxicity, oxidative stress and inflammation, the main pathophysiological events in the course of mood disorders. Research indicates that PrPc may be a promising biomarker of cognitive decline. There is an urgent need of human studies to elucidate its potential utility in clinical practice.


Assuntos
Síndrome de Creutzfeldt-Jakob , Proteínas PrPC , Príons , Humanos , Síndrome de Creutzfeldt-Jakob/metabolismo , Transtornos do Humor , Plasticidade Neuronal , Príons/metabolismo , Transmissão Sináptica
7.
Prion ; 18(1): 28-39, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38512820

RESUMO

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These proteins typically contain prion-like domains of low complexity (PrLDs or LCDs) that govern their assembly into either functional or pathological amyloid fibrils. To date, over 60 mutations targeting the LCDs of hnRNPs have been identified and associated with a spectrum of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). The cryo-EM structures of pathological and functional fibrils formed by different hnRNPs have been recently elucidated, including those of hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, and FUS. In this review, we discuss the structural features of these amyloid assemblies, placing particular emphasis on scrutinizing the impact of prevalent disease-associated mutations mapping within their LCDs. By performing systematic energy calculations, we reveal a prevailing trend of destabilizing effects induced by these mutations in the amyloid structure, challenging the traditionally assumed correlation between pathogenicity and amyloidogenic propensity. Understanding the molecular basis of this discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B , Príons , Humanos , Príons/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Mutação
8.
Science ; 383(6689): 1284-1289, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38513035

RESUMO

Can the course of fatal prion diseases be changed by removing the protein before it goes bad?


Assuntos
Doenças Priônicas , Príons , Humanos , Doenças Priônicas/metabolismo
9.
J Phys Chem Lett ; 15(8): 2117-2122, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38363235

RESUMO

The misfolding of the α-helical cellular prion protein into a self-propagating ß-rich aggregated form is a key pathogenic event in fatal and transmissible neurodegenerative diseases collectively known as prion diseases. Herein, we utilize the interfacial properties of liquid crystals (LCs) to monitor the lipid-membrane-induced conformational switching of prion protein (PrP) into ß-rich amyloid fibrils. The lipid-induced conformational switching resulting in aggregation occurs at the nanomolar protein concentration and is primarily mediated by electrostatic interactions between PrP and lipid headgroups. Our LC-based methodology offers a potent and sensitive tool to detect and delineate molecular mechanisms of PrP misfolding mediated by lipid-protein interactions at the aqueous interface under physiological conditions.


Assuntos
Cristais Líquidos , Doenças Priônicas , Príons , Humanos , Proteínas Priônicas/química , Príons/química , Príons/metabolismo , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Peptídeos beta-Amiloides , Amiloide/química , Lipídeos , Dobramento de Proteína
10.
Transfusion ; 64 Suppl 1: S4-S18, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38394039
11.
Neuropathol Appl Neurobiol ; 50(1): e12963, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38353056

RESUMO

AIM: CH1641 was discovered in 1970 as a scrapie isolate that was unlike all other classical strains of scrapie isolated so far. We performed bio-assays of CH1641 in mice in order to further characterise this specific isolate. METHODS: We inoculated the original CH1641 isolate into ovine and bovine prion protein (PrP) transgenic mice as well as wild-type mice. In addition, we performed cross- and back passages between the various mouse lines to examine if one identical prion strain was isolated in all mouse lines or whether multiple prion strains exist in CH1641. RESULTS: We report the first successful transmission of CH1641 to wild-type RIII mice and via RIII mice to wild-type VM mice. Unexpectedly, analysis of the protease-resistant prion protein (PrPres ) in wild-type mice showed a classical scrapie banding pattern differing from the banding pattern of the original CH1641 isolate. Cross- and back passages of CH1641 between the various mouse lines confirmed that the same prion strain had been isolated in all mouse lines. CONCLUSIONS: The CH1641 isolate consists of a single prion strain but its molecular banding pattern of PrPres differs between wild-type mice and PrP transgenic mice. Consequently, molecular banding patterns of PrPres should be used with caution in strain typing since they do not solely depend on the properties of the prion strain but also on the host prion protein.


Assuntos
Príons , Scrapie , Camundongos , Animais , Bovinos , Ovinos , Príons/metabolismo , Scrapie/metabolismo , Proteínas Priônicas/genética , Proteínas PrPSc/metabolismo , Camundongos Transgênicos
12.
PLoS Genet ; 20(2): e1011194, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38422160

RESUMO

Misfolded proteins are usually refolded to their functional conformations or degraded by quality control mechanisms. When misfolded proteins evade quality control, they can be sequestered to specific sites within cells to prevent the potential dysfunction and toxicity that arises from protein aggregation. Btn2 and Hsp42 are compartment-specific sequestrases that play key roles in the assembly of these deposition sites. Their exact intracellular functions and substrates are not well defined, particularly since heat stress sensitivity is not observed in deletion mutants. We show here that Btn2 and Hsp42 are required for tolerance to oxidative stress conditions induced by exposure to hydrogen peroxide. Btn2 and Hsp42 act to sequester oxidized proteins into defined PQC sites following ROS exposure and their absence leads to an accumulation of protein aggregates. The toxicity of protein aggregate accumulation causes oxidant sensitivity in btn2 hsp42 sequestrase mutants since overexpression of the Hsp104 disaggregase rescues oxidant tolerance. We have identified the Sup35 translation termination factor as an in vivo sequestrase substrate and show that Btn2 and Hsp42 act to suppress oxidant-induced formation of the yeast [PSI+] prion, which is the amyloid form of Sup35. [PSI+] prion formation in sequestrase mutants does not require IPOD (insoluble protein deposit) localization which is the site where amyloids are thought to undergo fragmentation and seeding to propagate their heritable prion form. Instead, both amorphous and amyloid Sup35 aggregates are increased in btn2 hsp42 mutants consistent with the idea that prion formation occurs at multiple intracellular sites during oxidative stress conditions in the absence of sequestrase activity. Taken together, our data identify protein sequestration as a key antioxidant defence mechanism that functions to mitigate the damaging consequences of protein oxidation-induced aggregation.


Assuntos
Príons , Proteínas de Saccharomyces cerevisiae , Agregados Proteicos/genética , Príons/genética , Príons/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Estresse Oxidativo/genética , Amiloide/metabolismo , Oxidantes/farmacologia , Oxidantes/metabolismo , Fatores de Terminação de Peptídeos/genética , Fatores de Terminação de Peptídeos/metabolismo
13.
BMC Genomics ; 25(1): 177, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355406

RESUMO

BACKGROUND: Prion diseases, also known as transmissible spongiform encephalopathies (TSEs) remain one of the deleterious disorders, which have affected several animal species. Polymorphism of the prion protein (PRNP) gene majorly determines the susceptibility of animals to TSEs. However, only limited studies have examined the variation in PRNP gene in different Nigerian livestock species. Thus, this study aimed to identify the polymorphism of PRNP gene in Nigerian livestock species (including camel, dog, horse, goat, and sheep). We sequenced the open reading frame (ORF) of 65 camels, 31 village dogs and 12 horses from Nigeria and compared with PRNP sequences of 886 individuals retrieved from public databases. RESULTS: All the 994 individuals were assigned into 162 haplotypes. The sheep had the highest number of haplotypes (n = 54), and the camel had the lowest (n = 7). Phylogenetic tree further confirmed clustering of Nigerian individuals into their various species. We detected five non-synonymous SNPs of PRNP comprising of G9A, G10A, C11G, G12C, and T669C shared by all Nigerian livestock species and were in Hardy-Weinberg Equilibrium (HWE). The amino acid changes in these five non-synonymous SNP were all "benign" via Polyphen-2 program. Three SNPs G34C, T699C, and C738G occurred only in Nigerian dogs while C16G, G502A, G503A, and C681A in Nigerian horse. In addition, C50T was detected only in goats and sheep. CONCLUSION: Our study serves as the first to simultaneously investigate the polymorphism of PRNP gene in Nigerian livestock species and provides relevant information that could be adopted in programs targeted at breeding for prion diseases resistance.


Assuntos
Doenças Priônicas , Príons , Scrapie , Animais , Cavalos/genética , Ovinos/genética , Cães , Príons/genética , Príons/metabolismo , Proteínas Priônicas/genética , Polimorfismo de Nucleotídeo Único , Gado/genética , Fases de Leitura Aberta , Filogenia , Camelus/genética , Doenças Priônicas/genética , Doenças Priônicas/veterinária , Cabras/genética , Cabras/metabolismo , Scrapie/genética
14.
PLoS One ; 19(2): e0299038, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38394122

RESUMO

OBJECTIVE: Neurofilament light chain (Nf-L) has been used to detect neuroaxonal damage in the brain caused by physical injury or disease. The purpose of this study was to determine if serum Nf-L could be used as a biomarker for pre-symptomatic detection of scrapie in sheep. METHODS: Four sheep with prion protein genotype AVQQ were intranasally inoculated with the classical scrapie strain x124. Blood was collected every 4 weeks until 44 weeks post-inoculation, at which point weekly collection commenced. Serum was analyzed using single molecule array (Quanterix SR-X) to evaluate Nf-L concentrations. RESULTS: Scrapie was confirmed in each sheep by testing homogenized brainstem at the level of the obex with a commercially available enzyme immunoassay. Increased serum Nf-L concentrations were identified above the determined cutoff during the last tenth of the respective incubation period for each sheep. Throughout the time course study, PrPSc accumulation was not detected antemortem by immunohistochemistry in rectal tissue at any timepoint for any sheep. RT-QuIC results were inconsistently positive throughout the timepoints tested for each sheep; however, each sheep had at least one timepoint detected positive. When assessing serum Nf-L utility using receiver operator characteristic curves against different clinical parameters, such as asymptomatic and symptomatic (pruritus or neurologic signs), results showed that Nf-L was most useful at being an indicator of disease only late in disease progression when neurologic signs were present. CONCLUSION: Serum Nf-L concentrations in the cohort of sheep increased as disease progressed; however, serum Nf-L did not increase during the presymptomatic window. The levels increased substantially throughout the final 10% of the animals' scrapie incubation period when other clinical signs were present. Serum Nf-L is not a reliable biomarker for pre-clinical detection of scrapie.


Assuntos
Príons , Scrapie , Humanos , Ovinos , Animais , Scrapie/genética , Proteínas PrPSc/metabolismo , Filamentos Intermediários/metabolismo , Príons/metabolismo , Encéfalo/metabolismo , Biomarcadores
15.
PLoS One ; 19(2): e0298095, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38394123

RESUMO

The PINK1/Parkin pathway of mitophagy has been implicated in the pathogenesis of Parkinson's disease. In prion diseases, a transmissible neurodegenerative disease caused by the misfolded and infectious prion protein (PrPSc), expression of both PINK1 and Parkin are elevated, suggesting that PINK1/Parkin mediated mitophagy may also play a role in prion pathogenesis. Using mice in which expression of either PINK1 (PINK1KO) or Parkin (ParkinKO) has been ablated, we analyzed the potential role of PINK1 and Parkin in prion pathogenesis. Prion infected PINK1KO and ParkinKO mice succumbed to disease more rapidly (153 and 150 days, respectively) than wild-type control C57Bl/6 mice (161 days). Faster incubation times in PINK1KO and ParkinKO mice did not correlate with altered prion pathology in the brain, altered expression of proteins associated with mitochondrial dynamics, or prion-related changes in mitochondrial respiration. However, the expression level of mitochondrial respiration Complex I, a major site for the formation of reactive oxygen species (ROS), was higher in prion infected PINK1KO and ParkinKO mice when compared to prion infected control mice. Our results demonstrate a protective role for PINK1/Parkin mitophagy during prion disease, likely by helping to minimize ROS formation via Complex I, leading to slower prion disease progression.


Assuntos
Doenças Neurodegenerativas , Doenças Priônicas , Príons , Camundongos , Animais , Mitofagia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Doenças Priônicas/genética
16.
Sci Rep ; 14(1): 3804, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360908

RESUMO

Chronic wasting disease (CWD) is a highly contagious, fatal neurodegenerative disease caused by infectious prions (PrPCWD) affecting wild and captive cervids. Although experimental feeding studies have demonstrated prions in feces of crows (Corvus brachyrhynchos), coyotes (Canis latrans), and cougars (Puma concolor), the role of scavengers and predators in CWD epidemiology remains poorly understood. Here we applied the real-time quaking-induced conversion (RT-QuIC) assay to detect PrPCWD in feces from cervid consumers, to advance surveillance approaches, which could be used to improve disease research and adaptive management of CWD. We assessed recovery and detection of PrPCWD by experimental spiking of PrPCWD into carnivore feces from 9 species sourced from CWD-free populations or captive facilities. We then applied this technique to detect PrPCWD from feces of predators and scavengers in free-ranging populations. Our results demonstrate that spiked PrPCWD is detectable from feces of free-ranging mammalian and avian carnivores using RT-QuIC. Results show that PrPCWD acquired in natural settings is detectable in feces from free-ranging carnivores, and that PrPCWD rates of detection in carnivore feces reflect relative prevalence estimates observed in the corresponding cervid populations. This study adapts an important diagnostic tool for CWD, allowing investigation of the epidemiology of CWD at the community-level.


Assuntos
Coiotes , Cervos , Doenças Neurodegenerativas , Príons , Doença de Emaciação Crônica , Animais , Fezes , Doença de Emaciação Crônica/diagnóstico , Doença de Emaciação Crônica/epidemiologia
17.
Prion ; 18(1): 11-27, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38323574

RESUMO

Creutzfeldt Jakob Disease (CJD) is a rapidly progressive, fatal neurodegenerative disorder, also known as a subacute spongiform encephalopathy. There are three major subtypes of CJD i.e. Sporadic CJD, which occurs for reasons unbeknown to science (85% of known cases), Genetic or Familial CJD which is characterized by the presence of mutations in the human prion protein (PRNP) gene (10-15% cases) and Iatrogenic CJD that occurs via accidental transmission through medical and surgical procedures (1-2% cases). CJD cases occur globally with 1 case per one million population/year. Considerable data is available related to the incidence and prevalence of CJD in Europe and America. However, the global surveillance database is yet to include Asia even though several Asian countries have their own CJD monitoring units. sCJD is the highest among all CJD cases in Asia. China (1957) and Japan (1705) have reported more cases of sCJD than any Asian country and Hong Kong (1) has reported the least. On the other hand, gCJD is highest in Japan (370) and least in India (2). Our analysis establishes the presence of all variants of CJD across Asia. However, in most Asian countries in general and Southeast Asian countries in particular, CJD cases are misdiagnosed and often underreported. Since Asia is the most populated continent in the world, the actual global prevalence of CJD cannot be estimated until and unless these countries are accounted for. Concrete and reliable surveillance networks are needed across Asia to evaluate the prevalence and incidence of CJD in the region. [Figure: see text]The graphical abstract demonstrates the prevalence of CJD cases in the world and systematically analyses the incidence of CJD in Asian countries between the year 1986-2022. Highest number of cases were reported in Japan followed by China. The study emphasizes the need for assimilation of Asian data in global prevalence.


Assuntos
Síndrome de Creutzfeldt-Jakob , Príons , Humanos , Síndrome de Creutzfeldt-Jakob/genética , Príons/genética , Proteínas Priônicas , Ásia
18.
BMJ Case Rep ; 17(2)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388201

RESUMO

Variably protease-sensitive prionopathy (VPSPr) is a recently characterised rare subtype of sporadic prion disease, mainly affecting individuals with valine homozygosity at codon 129 in the prion protein gene, with only seven methionine homozygote cases reported to date. This case presents clinical, neuropathological and biochemical features of the eighth VPSPr case worldwide with methionine homozygosity at codon 129 and compares the features with the formerly presented cases.The patient, a woman in her 70s, presented with cognitive decline, impaired balance and frequent falls. Medical history and clinical presentation were suggestive of a rapidly progressive dementia disorder. MRI showed bilateral thalamic hyperintensity. Cerebrospinal fluid real-time quaking-induced conversion was negative, and the electroencephalogram was unremarkable. The diagnosis was established through post-mortem pathological examinations. VPSPr should be suspected in rapidly progressive dementia lacking typical features or paraclinical results of protein misfolding diseases.


Assuntos
Síndrome de Creutzfeldt-Jakob , Demência , Doenças Priônicas , Príons , Feminino , Humanos , Príons/genética , Príons/metabolismo , Proteínas Priônicas/genética , Proteínas Priônicas/metabolismo , Metionina/genética , Metionina/metabolismo , Homozigoto , Encéfalo/patologia , Doenças Priônicas/genética , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Demência/genética , Racemetionina/metabolismo , Códon/genética , Códon/metabolismo , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia
19.
BMC Cancer ; 24(1): 199, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38347462

RESUMO

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor that exhibits resistance to current treatment, making the identification of novel therapeutic targets essential. In this context, cellular prion protein (PrPC) stands out as a potential candidate for new therapies. Encoded by the PRNP gene, PrPC can present increased expression levels in GBM, impacting cell proliferation, growth, migration, invasion and stemness. Nevertheless, the exact molecular mechanisms through which PRNP/PrPC modulates key aspects of GBM biology remain elusive. METHODS: To elucidate the implications of PRNP/PrPC in the biology of this cancer, we analyzed publicly available RNA sequencing (RNA-seq) data of patient-derived GBMs from four independent studies. First, we ranked samples profiled by bulk RNA-seq as PRNPhigh and PRNPlow and compared their transcriptomic landscape. Then, we analyzed PRNP+ and PRNP- GBM cells profiled by single-cell RNA-seq to further understand the molecular context within which PRNP/PrPC might function in this tumor. We explored an additional proteomics dataset, applying similar comparative approaches, to corroborate our findings. RESULTS: Functional profiling revealed that vesicular dynamics signatures are strongly correlated with PRNP/PrPC levels in GBM. We found a panel of 73 genes, enriched in vesicle-related pathways, whose expression levels are increased in PRNPhigh/PRNP+ cells across all RNA-seq datasets. Vesicle-associated genes, ANXA1, RAB31, DSTN and SYPL1, were found to be upregulated in vitro in an in-house collection of patient-derived GBM. Moreover, proteome analysis of patient-derived samples reinforces the findings of enhanced vesicle biogenesis, processing and trafficking in PRNPhigh/PRNP+ GBM cells. CONCLUSIONS: Together, our findings shed light on a novel role for PrPC as a potential modulator of vesicle biology in GBM, which is pivotal for intercellular communication and cancer maintenance. We also introduce GBMdiscovery, a novel user-friendly tool that allows the investigation of specific genes in GBM biology.


Assuntos
Glioblastoma , Príons , Humanos , Expressão Gênica , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Proteínas Priônicas/genética , Proteínas Priônicas/metabolismo , Príons/genética , Príons/metabolismo , Proteínas rab de Ligação ao GTP/genética , Sinaptofisina/metabolismo
20.
Nat Commun ; 15(1): 1168, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326345

RESUMO

Prion-like domains (PLDs) are low-complexity protein sequences enriched within nucleic acid-binding proteins including those involved in transcription and RNA processing. PLDs of FUS and EWSR1 play key roles in recruiting chromatin remodeler mammalian SWI/SNF (mSWI/SNF) complex to oncogenic FET fusion protein condensates. Here, we show that disordered low-complexity domains of multiple SWI/SNF subunits are prion-like with a strong propensity to undergo intracellular phase separation. These PLDs engage in sequence-specific heterotypic interactions with the PLD of FUS in the dilute phase at sub-saturation conditions, leading to the formation of PLD co-condensates. In the dense phase, homotypic and heterotypic PLD interactions are highly cooperative, resulting in the co-mixing of individual PLD phases and forming spatially homogeneous condensates. Heterotypic PLD-mediated positive cooperativity in protein-protein interaction networks is likely to play key roles in the co-phase separation of mSWI/SNF complex with transcription factors containing homologous low-complexity domains.


Assuntos
Príons , Animais , Príons/metabolismo , Fatores de Transcrição/metabolismo , Cromatina , Mamíferos/genética , Montagem e Desmontagem da Cromatina
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