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Cell and Tissue Research Apr 2023The fascinating history of prion diseases is intimately linked to the use of nonhuman primates as experimental models, which brought so fundamental and founding... (Review)
Review
The fascinating history of prion diseases is intimately linked to the use of nonhuman primates as experimental models, which brought so fundamental and founding information about transmissibility, pathogenesis, and resistance of prions. These models are still of crucial need for risk assessment of human health and may contribute to pave a new way towards the moving field of prion-like entities which now includes the main human neurodegenerative diseases (especially Alzheimer's and Parkinson's diseases).
Topics: Animals; Humans; Prion Diseases; Prions; Primates; Neurodegenerative Diseases; Parkinson Disease
PubMed: 35661921
DOI: 10.1007/s00441-022-03644-7 -
Journal of Neurochemistry Apr 2020Prions, which cause fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease, are misfolded and infectious protein aggregates. Currently, there are no... (Review)
Review
Prions, which cause fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease, are misfolded and infectious protein aggregates. Currently, there are no treatments available to halt or even delay the progression of prion disease in the brain. The infectious nature of prions has resulted in animal paradigms that accurately recapitulate all aspects of prion disease, and these have proven to be instrumental for testing the efficacy of candidate therapeutics. Nonetheless, infection of cultured cells with prions provides a much more powerful system for identifying molecules capable of interfering with prion propagation. Certain lines of cultured cells can be chronically infected with various types of mouse prions, and these models have been used to unearth candidate anti-prion drugs that are at least partially efficacious when administered to prion-infected rodents. However, these studies have also revealed that not all types of prions are equal, and that drugs active against mouse prions are not necessarily effective against prions from other species. Despite some recent progress, the number of cellular models available for studying non-mouse prions remains limited. In particular, human prions have proven to be particularly challenging to propagate in cultured cells, which has severely hindered the discovery of drugs for Creutzfeldt-Jakob disease. In this review, we summarize the cellular models that are presently available for discovering and testing drugs capable of blocking the propagation of prions and highlight challenges that remain on the path towards developing therapies for prion disease.
Topics: Animals; Cells, Cultured; Humans; In Vitro Techniques; Prion Diseases; Prions
PubMed: 31943194
DOI: 10.1111/jnc.14956 -
Epilepsy & Behavior : E&B Feb 2021Epileptic seizures have been described as one feature of prion diseases, but are an unusual clinical presentation. The aim of this narrative Review was to summarize... (Review)
Review
Epileptic seizures have been described as one feature of prion diseases, but are an unusual clinical presentation. The aim of this narrative Review was to summarize current knowledge of epileptic seizures in the various forms of prion diseases, from a clinical perspective. Examination of the published literature identified no systematic studies; the evidence base is largely anecdotal, consisting mainly of case studies and small case series. Hence, uncertainty prevails as to seizure frequency, semiology, treatment, and pathogenesis in prion diseases. Seizures probably occur in around 10% of sporadic cases but less frequently in iatrogenic and familial forms, with the possible exception of the E200K mutation. The literature suggests a predominance of focal motor and nonconvulsive status epilepticus. Electroencephalographic accompaniments include periodic lateralized or generalized periodic epileptiform discharges (PLEDs, GPEDs), sometimes predating the more typical periodic sharp wave complexes. There are no convincing accounts of successful antiepileptic drug therapy. The underlying mechanisms of epileptogenesis in prion diseases may include loss of cellular prion protein function (PrP) and aggregation of abnormally folded prion protein (PrP). The need for systematic studies and clinical trials to expand the evidence base surrounding epilepsy and prion diseases is evident.
Topics: Creutzfeldt-Jakob Syndrome; Epilepsy; Humans; Prion Diseases; Prions; Seizures
PubMed: 33309427
DOI: 10.1016/j.yebeh.2020.107630 -
Expert Review of Neurotherapeutics 2023Before the introduction of MRI diffusion-weighted images (DWI), the diagnosis of Creutzfeldt-Jakob disease (CJD) relied upon nonspecific findings including clinical... (Review)
Review
INTRODUCTION
Before the introduction of MRI diffusion-weighted images (DWI), the diagnosis of Creutzfeldt-Jakob disease (CJD) relied upon nonspecific findings including clinical symptoms, EEG abnormalities, and elevated levels of cerebrospinal fluid 14-3-3 protein. Subsequently, the use of DWI has improved diagnostic accuracy, but it sometimes remains difficult to differentiate CJD from encephalitis, epilepsy, and other dementing disorders. The revised diagnostic criteria include real-time quaking-induced conversion (RT-QuIC), detecting small amounts of CJD-specific prion protein, and clinically sensitive DWI. Combining these techniques has further improved diagnostic accuracy, enabling earlier diagnosis.
AREAS COVERED
Herein, the authors review the recent advances in diagnostic methods and revised diagnostic criteria for sporadic CJD. They also discuss other prion diseases, such as variant CJD and chronic wasting disease, where the emergence of new types is a concern.
EXPERT OPINION
Despite improvements in diagnostic methods and criteria, some subtypes of prion disease are still difficult to diagnose, and even the diagnosis using the most innovative RT-QuIC test remains a challenge in terms of accuracy and standardization. However, these revised criteria can be adapted to the emergence of new types of prion diseases. It is essential to continue careful surveillance and update information on the latest prion disease phenotypes.
Topics: Humans; Creutzfeldt-Jakob Syndrome; Prion Diseases; Early Diagnosis; Encephalitis; Phenotype
PubMed: 37581576
DOI: 10.1080/14737175.2023.2246653 -
Journal of Enzyme Inhibition and... Dec 2023Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP) that forms insoluble...
Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP) that forms insoluble amyloids to impair brain function. PrP interacts with the non-pathogenic, cellular prion protein (PrP) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrP but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds and showed almost perfect inhibition (EC = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates and one of them decreased the level of PrP in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.
Topics: Humans; Prions; Prion Proteins; Brain; Prion Diseases; Cells, Cultured
PubMed: 36950944
DOI: 10.1080/14756366.2023.2191164 -
The Journal of Biological Chemistry Nov 2023Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant...
Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant cellular prion protein (PrP) to β-sheet-rich pathological aggregated form of PrP in many mammalian species. Dogs exhibit resistance to prion diseases, but the mechanism behind the phenomenon remains poorly understood. Compared with human PrP and mouse PrP, dog PrP has two unique amino acid residues, Arg177 and Asp159. Because PrP contains a low-complexity and intrinsically disordered region in its N-terminal domain, it undergoes liquid-liquid phase separation (LLPS) in vitro and forms protein condensates. However, little is known about whether these two unique residues modulate the formation of PrP condensates. Here, using confocal microscopy, fluorescence recovery after photobleaching assays, thioflavin T binding assays, and transmission electron microscopy, we report that Arg177 and Asp159 from the dog PrP slow the LLPS of full-length human PrP, shifting the equilibrium phase boundary to higher protein concentrations and inhibit amyloid formation of the human protein. In sharp contrast, His177 and Asn159 from the human PrP enhance the LLPS of full-length dog PrP, shifting the equilibrium phase boundary to lower protein concentrations, and promote fibril formation of the canid protein. Collectively, these results demonstrate how LLPS and amyloid formation of PrP are inhibited by a single residue Arg177 or Asp159 associated with prion disease resistance, and how LLPS and fibril formation of PrP are promoted by a single residue His177 or Asn159. Therefore, Arg177/His177 and Asp159/Asn159 are key residues in modulating PrP liquid-phase condensation.
Topics: Mice; Dogs; Humans; Animals; Prion Proteins; Prions; Amyloid; Amyloidogenic Proteins; Prion Diseases; Mammals
PubMed: 37805139
DOI: 10.1016/j.jbc.2023.105329 -
Nature Reviews. Disease Primers Feb 2024
Topics: Humans; Creutzfeldt-Jakob Syndrome; Prion Diseases; Brain
PubMed: 38424445
DOI: 10.1038/s41572-024-00506-0 -
Cell and Tissue Research Apr 2023Chronic wasting disease (CWD) is a fatal neurodegenerative prion disease of cervid species including deer, elk, moose and reindeer. The disease has shown both geographic... (Review)
Review
Chronic wasting disease (CWD) is a fatal neurodegenerative prion disease of cervid species including deer, elk, moose and reindeer. The disease has shown both geographic and species expansion since its discovery in the late 1960's and is now recognized in captive and free-ranging cervid populations in North America, Asia and Europe. The facile transmission of CWD is unique among prion diseases and has resulted in growing concern for cervid populations and human public health. The development of native cervid host models with longitudinal monitoring has revealed new insights about CWD pathogenesis and transmission dynamics. More than 20 years of experimental studies conducted in these models, using biologically relevant routes of infection, have led to better understanding of many aspect of CWD infections. This review addresses some of these insights, including: (i) the temporal intra-host trafficking of CWD prions in tissues and bodily fluids, (ii) the presence of infectivity shed in bodily excretions that may help explain the facile transmission of CWD, (iii) mother-to-offspring CWD transmission, (iv) the influence of some Prnp polymorphisms on CWD susceptibility, and (vi) continued development of vaccine strategies to mitigate CWD.
Topics: Humans; Animals; Wasting Disease, Chronic; Deer; Prions; Prion Proteins; Models, Animal
PubMed: 35113219
DOI: 10.1007/s00441-022-03590-4 -
Cell and Tissue Research Apr 2023Prion diseases, also known as transmissible spongiform encephalopathies, are caused by the accumulation of abnormal isoforms of the prion protein (scrapie isoform of the... (Review)
Review
Prion diseases, also known as transmissible spongiform encephalopathies, are caused by the accumulation of abnormal isoforms of the prion protein (scrapie isoform of the prion protein, PrPSc) in the central nervous system. Many compounds with anti-prion activities have been found using in silico screening, in vitro models, persistently prion-infected cell models, and prion-infected rodent models. Some of these compounds include several types of polymers. Although the inhibition or removal of PrPSc production is the main target of therapy, the unique features of prions, namely protein aggregation and assembly accompanied by steric structural transformation, may require different strategies for the development of anti-prion drugs than those for conventional therapeutics targeting enzyme inhibition, agonist ligands, or modulation of signaling. In this paper, we first overview the history of the application of polymers to prion disease research. Next, we describe the characteristics of each type of polymer with anti-prion activity. Finally, we discuss the common features of these polymers. Although drug delivery of these polymers to the brain is a challenge, they are useful not only as leads for therapeutic drugs but also as tools to explore the structure of PrPSc and are indispensable for prion disease research.
Topics: Animals; Sheep; Prion Proteins; Polymers; Prion Diseases; Scrapie; Prions
PubMed: 35307792
DOI: 10.1007/s00441-022-03604-1 -
Redox Biology Jun 2024Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are protein-based neurodegenerative disorders (NDs) affecting humans and animals. They...
Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are protein-based neurodegenerative disorders (NDs) affecting humans and animals. They are characterized by the conformational conversion of the normal cellular prion protein, PrP, into the pathogenic isoform, PrP. Prion diseases are invariably fatal and despite ongoing research, no effective prophylactic or therapeutic avenues are currently available. Anthocyanins (ACNs) are unique flavonoid compounds and interest in their use as potential neuroprotective and/or therapeutic agents against NDs, has increased significantly in recent years. Therefore, we investigated the potential anti-oxidant and anti-prion effects of Oenin and Myrtillin, two of the most common anthocyanins, using the most accepted in the field overexpressing PrPin vitro model and a cell free protein aggregation model. Our results, indicate both anthocyanins as strong anti-oxidant compounds, upregulating the expression of genes involved in the anti-oxidant response, and reducing the levels of Reactive Oxygen Species (ROS), produced due to pathogenic prion infection, through the activation of the Keap1-Nrf2 pathway. Importantly, they showcased remarkable anti-prion potential, as they not only caused the clearance of pathogenic PrP aggregates, but also completely inhibited the formation of PrP fibrils in the Cerebrospinal Fluid (CSF) of patients with Creutzfeldt-Jakob disease (CJD). Therefore, Oenin and Myrtillin possess pleiotropic effects, suggesting their potential use as promising preventive and/or therapeutic agents in prion diseases and possibly in the spectrum of neurodegenerative proteinopathies.
Topics: Anthocyanins; Humans; Reactive Oxygen Species; NF-E2-Related Factor 2; Antioxidants; Prion Diseases; Kelch-Like ECH-Associated Protein 1; Animals; PrPSc Proteins; Signal Transduction
PubMed: 38565068
DOI: 10.1016/j.redox.2024.103133