-
Current Opinion in Pharmacology Feb 2019Prion-related encephalopathies or transmissible spongiform encephalopathies (TSEs) are a group of rare progressive neurodegenerative disorders that are invariably fatal... (Review)
Review
Prion-related encephalopathies or transmissible spongiform encephalopathies (TSEs) are a group of rare progressive neurodegenerative disorders that are invariably fatal with often only six months elapsing from diagnosis to patient death. This makes the development of effective therapeutic strategies challenging. Nonetheless, compounds have been identified in animal models of TSE that prolong survival and, in some instances, eradicate the disease. These have been tested in the clinic, although with modest or negative outcomes. While little progress has been made over the last decade, new findings that include the ability to identify prion aggregates at low levels in biological fluids and cells may lead to the development of early-stage biomarkers for TSE. An increased focus on immunotherapeutic approaches to TSE may result in the development of novel preventive approaches for TSE.
Topics: Animals; Doxycycline; Humans; Immunotherapy; Prion Diseases
PubMed: 31108459
DOI: 10.1016/j.coph.2019.04.019 -
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 -
Viruses Mar 2019Prion diseases are a unique group of rare neurodegenerative disorders characterized by tissue deposition of heterogeneous aggregates of abnormally folded... (Review)
Review
Prion diseases are a unique group of rare neurodegenerative disorders characterized by tissue deposition of heterogeneous aggregates of abnormally folded protease-resistant prion protein (PrP), a broad spectrum of disease phenotypes and a variable efficiency of disease propagation in vivo. The dominant clinicopathological phenotypes of human prion disease include Creutzfeldt⁻Jakob disease, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann⁻Sträussler⁻Scheinker disease. Prion disease propagation into susceptible hosts led to the isolation and characterization of prion strains, initially operatively defined as "isolates" causing diseases with distinctive characteristics, such as the incubation period, the pattern of PrP distribution, and the regional severity of neuropathological changes after injection into syngeneic hosts. More recently, the structural basis of prion strains has been linked to amyloid polymorphs (i.e., variant amyloid protein conformations) and the concept extended to all protein amyloids showing polymorphic structures and some evidence of in vivo or in vitro propagation by seeding. Despite the significant advances, however, the link between amyloid structure and disease is not understood in many instances. Here we reviewed the most significant contributions of human prion disease studies to current knowledge of the molecular basis of phenotypic variability and the prion strain phenomenon and underlined the unsolved issues from the human disease perspective.
Topics: Biological Variation, Population; Genetic Variation; Humans; Prion Diseases; Prion Proteins; Protein Aggregates; Protein Conformation
PubMed: 30934971
DOI: 10.3390/v11040309 -
Current Opinion in Pharmacology Feb 2019Human prion diseases are usually rapid neurodegenerative illnesses that are invariably fatal. Despite several clinical trials, no effective treatment has been discovered... (Review)
Review
Human prion diseases are usually rapid neurodegenerative illnesses that are invariably fatal. Despite several clinical trials, no effective treatment has been discovered in humans. Although prior clinical trials have not been successful, they provided information that is vital for the formation of future clinical trials. Among these findings is the realization that there are several prion disease-specific aspects that must be considered when conducting clinical trials. The rarity, rapidity, and clinical heterogeneity of prion disease affect study enrollment and the ability to measure treatment effects. In addition to affecting results, study methodology may also influence study enrollment. In this review, we explore several challenges to conducting clinical trials in prion disease and suggest some practical considerations.
Topics: Animals; Clinical Trials as Topic; Humans; Prion Diseases
PubMed: 30508662
DOI: 10.1016/j.coph.2018.11.006 -
Neuropathology : Official Journal of... Oct 2020This review considers whether the Braak hypothesis on protein propagation could account for prion disease, particularly Creutzfeldt-Jakob disease (CJD). In CJD, we can... (Review)
Review
This review considers whether the Braak hypothesis on protein propagation could account for prion disease, particularly Creutzfeldt-Jakob disease (CJD). In CJD, we can speculate on the pathological onset region to some degree in reference to the clinical symptoms and magnetic resonance imaging findings. Although relating the Braak hypothesis to prion disease is not straightforward, the following could be proposed based on experimental and previously reported case observations. Pathogenic abnormal prion protein (PrP) deposition in the central nervous system (CNS) probably begins several months or years before clinical symptom onset, signifying the potentiality of a preclinical stage, similar to α-synuclein deposition in Parkinson's disease (PD) and amyloid-β/tau deposition in Alzheimer's disease (AD). Unlike in PD and AD, the initial clinical symptoms of CJD vary by case, and thus the onset lesions must also be various and multiple in the CNS. Based on the pathological findings, particularly of PrP deposition extensively observed in the CNS gray matter of autopsy cases, it could be speculated that in the early disease stage, including the preclinical stage, abnormal PrP spreads from the onset region without directionality or hierarchy. Because each CNS region shows either vulnerability to or resistance against PrP deposition and pathological progression in prion disease, the lesion distribution shows system degeneration. Although pathologically combined cases of type 1 and type 2 PrP patterns are often recognized, type 1 and type 2 PrP patterns must never shift toward each other during the disease course; in other words, the original type of PrP deposition in each region presumably remains unchanged in each case. According to the several observations and corresponding speculations, there are at least partial similarities between prion disease and protein propagation, as explained by the Braak hypothesis, in terms of pathological lesion progression, but several noted contradictions preclude the hypothesis from comprehensively accounting for prion disease.
Topics: Animals; Brain; Creutzfeldt-Jakob Syndrome; Humans; Models, Neurological; Neurons; Prion Diseases
PubMed: 32363728
DOI: 10.1111/neup.12654 -
Neurologic Clinics Aug 2007Prion diseases are a unique group of neurologic diseases caused by an abnormal protein conformation. Prion diseases encompass genetic, sporadic, iatrogenic, and acquired... (Review)
Review
Prion diseases are a unique group of neurologic diseases caused by an abnormal protein conformation. Prion diseases encompass genetic, sporadic, iatrogenic, and acquired conditions in humans and other mammals. Although they are relatively rare, they produce a diverse array of symptoms, uniformly are fatal, and provide important information about proteins and degenerative neurobiology in addition to lessons about animal and human food chains.
Topics: Animals; Disease Outbreaks; Humans; Prion Diseases; Prions
PubMed: 17659192
DOI: 10.1016/j.ncl.2007.03.006 -
International Ophthalmology Clinics 2007
Review
Topics: Animals; Diagnosis, Differential; Genetic Predisposition to Disease; Humans; Prion Diseases; Risk Factors
PubMed: 18049285
DOI: 10.1097/IIO.0b013e318157241a -
Progress in Molecular Biology and... 2020The transmission of prions between species is typically an inefficient process due to the species barrier, which represents incompatibility between prion seed and... (Review)
Review
The transmission of prions between species is typically an inefficient process due to the species barrier, which represents incompatibility between prion seed and substrate molecules. Bank voles (Myodes glareolus) are an exception to this rule, as they are susceptible to a diverse range of prion strains from many different animal species. In particular, bank voles can be efficiently infected with most types of human prions and have played a critical role in validating variably protease-sensitive prionopathy (VPSPr) and certain forms of Gerstmann-Sträussler-Scheinker (GSS) disease as bona fide prion disorders rather than non-transmissible proteinopathies. The bank vole prion protein (BVPrP) confers a "universal prion acceptor" phenotype when expressed in mice and when used as a substrate for in vitro prion amplification assays, indicating that the unique prion transmission properties of bank voles are mediated by BVPrP. Over-expression of BVPrP in mice can also promote the spontaneous development of prion disease, indicating that BVPrP is intrinsically prone to both spontaneous and template-directed misfolding. Here, we discuss the utility of bank voles and BVPrP for prion research and how they have provided new tools for establishing rapid animal bioassays, modeling spontaneous prion disease, standardizing prion diagnostics, and understanding the molecular basis of the species barrier.
Topics: Amino Acid Sequence; Animals; Arvicolinae; Disease Models, Animal; Disease Susceptibility; Prion Diseases; Prions
PubMed: 32958232
DOI: 10.1016/bs.pmbts.2020.08.009 -
Essays in Biochemistry 2014Prion disease is the only naturally occurring infectious protein misfolding disorder. The chemical nature of the infectious agent has been debated for more than half a... (Review)
Review
Prion disease is the only naturally occurring infectious protein misfolding disorder. The chemical nature of the infectious agent has been debated for more than half a century. Early studies on scrapie suggested that the unusual infectious agent might propagate in the absence of nucleic acid. The 'protein-only hypothesis' provides a theoretical model to explain how a protein self-replicates without nucleic acid, which predicts that a prion, the proteinaceous infectious agent, propagates by converting its normal counterpart into the likeness of itself. Decades of studies have provided overwhelming evidence to support this hypothesis. The latest advances in generating infectious prions with bacterially expressed recombinant prion protein in the presence of cofactors not only provide convincing evidence supporting the 'protein-only hypothesis', but also indicate a role of cofactors in forming prion infectivity and encoding prion strains. In the present chapter, we review the literature regarding the chemical nature of the infectious agent, describe recent achievements in proving the 'protein-only hypothesis', and discuss the remaining questions in this research area.
Topics: Animals; Humans; Prion Diseases; Prions; Protein Folding
PubMed: 25131595
DOI: 10.1042/bse0560181 -
Infectious Disorders Drug Targets Apr 2012Prion diseases, also known as transmissible spongiform encephalopathies, are invariably fatal neurodegenerative diseases for which there are no efficacious treatments.... (Review)
Review
Prion diseases, also known as transmissible spongiform encephalopathies, are invariably fatal neurodegenerative diseases for which there are no efficacious treatments. Thousands of compounds have been screened for anti-prion effect, and yet of those that have effect in vitro, very few show effect in vivo, especially if administered in the later stages of disease. However, with new techniques for early diagnosis being developed, and with further insight into the pathogenesis of early disease, including the role of oligomers and the contribution of accessory molecules and signalling cascades, the chance of finding a therapeutic strategy is increasing. Beyond clinical therapy, there is increasing need to find effective decontaminants for blood supplies, as variant Creutzfeldt Jakob Disease (vCJD) is transmissible by blood. Non-toxic preventative therapies are also needed, with ongoing cases of Bovine Spongiform Encephalopathy (BSE) and the spread of Chronic Wasting Disease (CWD) being a growing concern. A primary target for therapy has been the conversion of the normal form of prion protein (PrPC) to its abnormal counterpart (PrPSc). Many of the chemotherapeutic agents with antiprion effect share structural similarities, often being polyanionic or polycyclic. They may directly bind PrPC or PrPSc, or they may redistribute, sequester, or down-regulate PrPC, thus preventing its conversion. There have also been some novel approaches, including trapping PrPSc in a multimeric form such that it can no longer cause conversion, increasing clearance of PrPSc, targeting accessory molecules which play a role in conversion, targeting pathways which lead to neurodegeneration, and stem cell therapy. It may be that a combination of compounds will be necessary for maximal effect and there is evidence that synergistic responses occur with dual therapy. This updated review focuses primarily on chemicalbased treatments in light of developments in diagnostic technologies, including results from recent clinical trials, and proposes some promising new targets for prion therapy.
Topics: Animals; Humans; Prion Diseases; Prions; Protein Folding
PubMed: 22420513
DOI: 10.2174/187152612800100161