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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 -
Nature Reviews. Disease Primers Feb 2024
Topics: Humans; Creutzfeldt-Jakob Syndrome; Prion Diseases; Brain
PubMed: 38424445
DOI: 10.1038/s41572-024-00506-0 -
Current Opinion in Pharmacology Feb 2019Prion diseases are devastating neurodegenerative disorders for which no drugs are available. The successful development of therapeutics depends on drug screening... (Review)
Review
Prion diseases are devastating neurodegenerative disorders for which no drugs are available. The successful development of therapeutics depends on drug screening platforms and preclinical models that recapitulate key molecular and pathological features of the disease. Innovative experimental tools have been developed over the last few years that might facilitate drug discovery, including cell-free prion replication assays and prion-infected flies. However, there is still room for improvement. Animal models of genetic prion disease are few, and only partially recapitulate the complexity of the human disorder. Moreover, we still lack a human cell culture model suitable for high-content anti-prion drug screening. This review provides an overview of the models currently used in prion research, and discusses their promise and limitations for drug discovery.
Topics: Animals; Biological Assay; Drug Discovery; Humans; In Vitro Techniques; Models, Biological; Prion Diseases
PubMed: 30878006
DOI: 10.1016/j.coph.2019.02.002 -
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 -
Nature Reviews. Neurology Feb 2015Prion diseases are typically recognized as rapidly progressive dementing illnesses that also feature myoclonus and cerebellar ataxia. Several families have now been... (Review)
Review
Prion diseases are typically recognized as rapidly progressive dementing illnesses that also feature myoclonus and cerebellar ataxia. Several families have now been described with a late-onset hereditary sensory and autonomic neuropathy caused by truncation of prion protein (PrP), and associated with systemic amyloidosis, which was a profoundly unexpected phenotype. The chronic symptoms of this disorder, termed PrP systemic amyloidosis, can be very disabling, and are comparable to familial amyloid polyneuropathy (FAP) caused by transthyretin mutations. Patients require symptomatic therapies directed towards control of nausea, diarrhoea, incontinence, neuropathic pain and postural hypotension. Although the potential transmissibility of this new prion disease is probably extremely low, we advocate PrP gene analysis before biopsy in the investigation of peripheral and autonomic neuropathies, or for patients with unexplained diarrhoea and neuropathy. Prion diseases and the FAPs both display prominent effects of mutation type on clinical presentation and patterns of pathology-a fascinating but unexplained observation. Several neurodegenerative diseases associated with central protein misfolding, such as Huntington and Parkinson diseases, also have under-recognized peripheral components. Most of the familial amyloidoses can be explained by known gene mutations, but amino acid variants in proteins involved in other central neurodegenerative diseases might direct the initial pathology to the periphery.
Topics: Amyloidosis; Diagnosis, Differential; Humans; Immunoglobulin Light-chain Amyloidosis; Prion Diseases
PubMed: 25623792
DOI: 10.1038/nrneurol.2014.263 -
Current Opinion in Neurology Jun 2015The present review discusses recent clinical data on diagnosis, new forms, and treatment of human prion diseases, and briefly summarizes research suggesting prion-like... (Review)
Review
PURPOSE OF REVIEW
The present review discusses recent clinical data on diagnosis, new forms, and treatment of human prion diseases, and briefly summarizes research suggesting prion-like mechanisms in other neurodegenerative diseases.
RECENT FINDINGS
When proper sequences are performed, MRI has high diagnostic utility in prion disease, but there are issues with interpretation of images. The spectrum of MRI's utility for diagnosis and understanding human prion disease is still being explored. Two recent diffusion tensor imaging studies quantified changes in the gray and white matter in sporadic Jakob-Creutzfeldt disease, with unexpected results. The diagnostic utility of cerebrospinal fluid biomarkers has been controversial. A few studies showed that amplification methods can detect prions in either cerebrospinal fluid, olfactory epithelium, blood and/or urine in various human prion diseases. Additional cases of variably protease-sensitive prionopathy have led to a broader understanding of this novel sporadic prion disease. A few new mutations causing genetic prion disease, one with a very atypical presentation, have been identified. Although recent human prion disease treatment trials did not show benefit, they have improved our understanding, and led to better quantification, of the progression of these disorders. Lastly, we briefly summarize the increasing evidence that many nonprion neurodegenerative proteinopathies might spread in the brain by a prion-like mechanism.
SUMMARY
New prion detection methods appear promising, but need to be replicated with larger sample sizes. Identification of novel forms of human prion disease might better elucidate the full spectrum of prion diseases and expand our understanding of their pathogenesis.
Topics: Creutzfeldt-Jakob Syndrome; Humans; Magnetic Resonance Imaging; Prions
PubMed: 25923128
DOI: 10.1097/WCO.0000000000000197 -
Progress in Molecular Biology and... 2017Transmissible spongiform encephalopathies (TSEs), or prions, are neurodegenerative diseases that affect a variety of animal species, including humans. Cruetzfeldt-Jakob... (Review)
Review
Transmissible spongiform encephalopathies (TSEs), or prions, are neurodegenerative diseases that affect a variety of animal species, including humans. Cruetzfeldt-Jakob disease (CJD) in humans, sheep and goat scrapie, chronic wasting disease (CWD) of cervids, and transmissible mink encephalopathy (TME) of mink are classified as TSEs. According to the "protein-only" hypothesis (Prusiner, 1982), prions are devoid of nucleic acids and consist of assemblies of misfolded host-encoded normal protein, the prion protein (PrP). Prion propagation is thought to occur by a templating mechanism during which PrP is recruited, converted to a disease-associated isoform (PrP), and assembled onto the growing amyloid fibril. This fibular assembly is infectious, with ability to initiate disease processes similar to other pathogenic agents. Evidence indicates that scrapie, CWD, and TME disease processes follow this rule.
Topics: Animals; Humans; Prion Diseases; Scrapie; Wasting Disease, Chronic; Zoonoses
PubMed: 28838664
DOI: 10.1016/bs.pmbts.2017.07.009 -
Cell and Tissue Research Apr 2023For over three decades, cultured cells have been a useful tool for dissecting the molecular details of prion replication and the identification of candidate therapeutics... (Review)
Review
For over three decades, cultured cells have been a useful tool for dissecting the molecular details of prion replication and the identification of candidate therapeutics for prion disease. A major issue limiting the translatability of these studies has been the inability to reliably propagate disease-relevant, non-mouse strains of prions in cells relevant to prion pathogenesis. In recent years, fueled by advances in gene editing technology, it has become possible to propagate prions from hamsters, cervids, and sheep in immortalized cell lines originating from the central nervous system. In particular, the use of CRISPR-Cas9-mediated gene editing to generate versions of prion-permissive cell lines that lack endogenous PrP expression has provided a blank canvas upon which re-expression of PrP leads to species-matched susceptibility to prion infection. When coupled with the ability to propagate prions in cells or organoids derived from stem cells, these next-generation cellular models should provide an ideal paradigm for identifying small molecules and other biological therapeutics capable of interfering with prion replication in animal and human prion disorders. In this review, we summarize recent advances that have widened the spectrum of prion strains that can be propagated in cultured cells and cutting-edge tissue-based models.
Topics: Cricetinae; Animals; Humans; Sheep; Prions; Prion Diseases; Cells, Cultured; Cell Line; Gene Editing; Deer
PubMed: 35581386
DOI: 10.1007/s00441-022-03630-z