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Cell and Tissue Research Apr 2023Real-time quaking-induced conversion (RT-QuIC) is a cell-free abnormal form of prion protein (PrP) amplification method using recombinant prion protein from Escherichia... (Review)
Review
Real-time quaking-induced conversion (RT-QuIC) is a cell-free abnormal form of prion protein (PrP) amplification method using recombinant prion protein from Escherichia coli that can measure prion seeding activity in samples with high sensitivity. The advantages of this method are that it is much more sensitive than Western blotting, which is usually used to detect PrP, and that prion seeding activity can be easily quantified by combining it with endpoint dilution of the sample, and that it can be amplified in most species and prion strains. A decade has passed since the development of RT-QuIC, and many studies have been reported that take advantage of its characteristics. In particular, its usefulness in the diagnosis of sporadic CJD has been clarified, and it is recommended to be one of the diagnostic criteria. Future challenges include the establishment of a method to differentiate prion strains and application of RT-QuIC to early diagnosis of prion diseases and determination of treatment efficacy.
Topics: Animals; Cattle; Prions; Prion Proteins; Creutzfeldt-Jakob Syndrome; Encephalopathy, Bovine Spongiform; Blotting, Western; Recombinant Proteins; Prion Diseases
PubMed: 35084571
DOI: 10.1007/s00441-021-03568-8 -
Current Opinion in Neurobiology Apr 2020Therapeutic strategies and study designs for neurodegenerative diseases have started to explore the potential of preventive treatment in healthy people, emphasising... (Review)
Review
Therapeutic strategies and study designs for neurodegenerative diseases have started to explore the potential of preventive treatment in healthy people, emphasising characterisation of biomarkers capable of indicating proximity to clinical onset. This need is even more pressing for individuals at risk of prion disease given its rarity which virtually precludes the probability of recruiting enough numbers for well powered preventive trials based on clinical endpoints. Experimental mouse inoculation studies have revealed a rapid exponential rise in infectious titres followed by a relative plateau of considerable duration before clinical onset. This clinically silent incubation period represents a potential window of opportunity for the adaptation of ultrasensitive prion seeding assays to define the onset of prion infection, and for neurodegenerative biomarker discovery through similarly sensitive digital immunoassay platforms.
Topics: Animals; Biomarkers; Prion Diseases; Prions
PubMed: 32109717
DOI: 10.1016/j.conb.2020.01.009 -
Cells Oct 2023Prion diseases are neurodegenerative disorders that are progressive, incurable, and deadly. The prion consists of PrP, the misfolded pathogenic isoform of the cellular... (Review)
Review
Prion diseases are neurodegenerative disorders that are progressive, incurable, and deadly. The prion consists of PrP, the misfolded pathogenic isoform of the cellular prion protein (PrP). PrP is involved in a variety of physiological functions, including cellular proliferation, adhesion, differentiation, and neural development. Prion protein is expressed on the membrane surface of a variety of stem cells (SCs), where it plays an important role in the pluripotency and self-renewal matrix, as well as in SC differentiation. SCs have been found to multiply the pathogenic form of the prion protein, implying their potential as an in vitro model for prion diseases. Furthermore, due to their capability to self-renew, differentiate, immunomodulate, and regenerate tissue, SCs are prospective cell treatments in many neurodegenerative conditions, including prion diseases. Regenerative medicine has become a new revolution in disease treatment in recent years, particularly with the introduction of SC therapy. Here, we review the data demonstrating prion diseases' biology and molecular mechanism. SC biology, therapeutic potential, and its role in understanding prion disease mechanisms are highlighted. Moreover, we summarize preclinical studies that use SCs in prion diseases.
Topics: Humans; Prion Proteins; Prion Diseases; Prions; Neurodegenerative Diseases; Stem Cells
PubMed: 37830627
DOI: 10.3390/cells12192413 -
International Journal of Molecular... Nov 2021Conformational conversion of the cellular isoform of prion protein, PrP, into the abnormally folded, amyloidogenic isoform, PrP, is an underlying pathogenic mechanism in... (Review)
Review
Conformational conversion of the cellular isoform of prion protein, PrP, into the abnormally folded, amyloidogenic isoform, PrP, is an underlying pathogenic mechanism in prion diseases. The diseases manifest as sporadic, hereditary, and acquired disorders. Etiological mechanisms driving the conversion of PrP into PrP are unknown in sporadic prion diseases, while prion infection and specific mutations in the PrP gene are known to cause the conversion of PrP into PrP in acquired and hereditary prion diseases, respectively. We recently reported that a neurotropic strain of influenza A virus (IAV) induced the conversion of PrP into PrP as well as formation of infectious prions in mouse neuroblastoma cells after infection, suggesting the causative role of the neuronal infection of IAV in sporadic prion diseases. Here, we discuss the conversion mechanism of PrP into PrP in different types of prion diseases, by presenting our findings of the IAV infection-induced conversion of PrP into PrP and by reviewing the so far reported transgenic animal models of hereditary prion diseases and the reverse genetic studies, which have revealed the structure-function relationship for PrP to convert into PrP after prion infection.
Topics: Animals; Cell Line, Tumor; Creutzfeldt-Jakob Syndrome; Gerstmann-Straussler-Scheinker Disease; Humans; Influenza A virus; Influenza, Human; Insomnia, Fatal Familial; Mice; Mice, Transgenic; Mutation; Neurons; PrPC Proteins; PrPSc Proteins; Prion Proteins; Protein Conformation; Reverse Genetics
PubMed: 34830321
DOI: 10.3390/ijms222212439 -
Swiss Medical Weekly Apr 2020The cellular prion protein (PrPC), a cell surface glycoprotein originally identified for its central role in prion diseases (also called transmissible spongiform... (Review)
Review
The cellular prion protein (PrPC), a cell surface glycoprotein originally identified for its central role in prion diseases (also called transmissible spongiform encephalopathies), has recently been implicated in the pathogenesis of other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases, by acting as a toxicity-transducing receptor for different misfolded protein isoforms, or in some case by exerting neuroprotective effects. Interestingly, PrPC has also been reported to play unexpected functions outside the nervous system, for example by contributing to myelin homeostasis, regulating specific processes of the immune system and participating in various aspects of cancer progression. Collectively, these observations point to a much broader role for PrPC in physiological and disease processes than originally assumed. In this manuscript, we provide an overview of what is known about the role of PrPC beyond prion disorders and discuss the potential implications of targeting this protein in different diseases.
Topics: Humans; Parkinson Disease; Prion Diseases; Prion Proteins; Prions
PubMed: 32330284
DOI: 10.4414/smw.2020.20222 -
Cell and Tissue Research Apr 2023Mammalian prions are lethal transmissible pathogens that cause fatal neurodegenerative diseases in humans and animals. They consist of fibrils of misfolded, host-encoded... (Review)
Review
Mammalian prions are lethal transmissible pathogens that cause fatal neurodegenerative diseases in humans and animals. They consist of fibrils of misfolded, host-encoded prion protein (PrP) which propagate through templated protein polymerisation. Prion strains produce distinct clinicopathological phenotypes in the same host and appear to be encoded by distinct misfolded PrP conformations and assembly states. Despite fundamental advances in our understanding of prion biology, key knowledge gaps remain. These include precise delineation of prion replication mechanisms, detailed explanation of the molecular basis of prion strains and inter-species transmission barriers, and the structural definition of neurotoxic PrP species. Central to addressing these questions is the determination of prion structure. While high-resolution definition of ex vivo prion fibrils once seemed unlikely, recent advances in cryo-electron microscopy (cryo-EM) and computational methods for 3D reconstruction of amyloids have now made this possible. Recently, near-atomic resolution structures of highly infectious, ex vivo prion fibrils from hamster 263K and mouse RML prion strains were reported. The fibrils have a comparable parallel in-register intermolecular β-sheet (PIRIBS) architecture that now provides a structural foundation for understanding prion strain diversity in mammals. Here, we review these new findings and discuss directions for future research.
Topics: Cricetinae; Humans; Mice; Animals; Prions; Cryoelectron Microscopy; Prion Proteins; Neurodegenerative Diseases; Mammals; Prion Diseases
PubMed: 36028585
DOI: 10.1007/s00441-022-03676-z -
Cell and Tissue Research Apr 2023Prion diseases are incurable, infectious and fatal neurodegenerative diseases that affect both humans and animals. The pathogenesis of prion disease involves the... (Review)
Review
Prion diseases are incurable, infectious and fatal neurodegenerative diseases that affect both humans and animals. The pathogenesis of prion disease involves the misfolding of the cellular prion protein, PrP, to a disease-causing conformation, PrP, in the brain. The exact mechanism of conversion of PrP to PrP is not clear; however, there are numerous studies supporting that this process of misfolding requires the association of PrP with lipid raft domains of the plasma membrane. An increase in the cellular cholesterol content with prion infection has been observed in both in vivo and in vitro studies. As cholesterol is critical for the formation of lipid rafts, on the one hand, this increase may be related to, or aiding in, the process of prion conversion. On the other hand, increased cholesterol levels may affect neuronal viability. Here, we discuss current literature on the underlying mechanisms and potential consequences of elevated neuronal cholesterol in prion infection and advancements in prion disease therapeutics targeting brain cholesterol homeostasis.
Topics: Animals; Humans; Prions; PrPSc Proteins; Prion Diseases; Prion Proteins; Cholesterol
PubMed: 35821439
DOI: 10.1007/s00441-022-03669-y -
International Journal of Molecular... Jan 2021Prion diseases are progressive and transmissive neurodegenerative diseases. The conformational conversion of normal cellular prion protein (PrP) into abnormal pathogenic... (Review)
Review
Prion diseases are progressive and transmissive neurodegenerative diseases. The conformational conversion of normal cellular prion protein (PrP) into abnormal pathogenic prion protein (PrP) is critical for its infection and pathogenesis. PrP possesses the ability to bind to various neurometals, including copper, zinc, iron, and manganese. Moreover, increasing evidence suggests that PrP plays essential roles in the maintenance of homeostasis of these neurometals in the synapse. In addition, trace metals are critical determinants of the conformational change and toxicity of PrP. Here, we review our studies and other new findings that inform the current understanding of the links between trace elements and physiological functions of PrP and the neurotoxicity of PrP.
Topics: Alzheimer Disease; Animals; Brain; Cations, Divalent; Copper; Homeostasis; Humans; Iron; Manganese; Neurons; PrPC Proteins; PrPSc Proteins; Prion Diseases; Protein Binding; Synapses; Synaptic Transmission; Zinc
PubMed: 33525334
DOI: 10.3390/ijms22031267 -
Cells Sep 2022Prion diseases are neurodegenerative diseases that affect humans and animals. They are always fatal and, to date, no treatment exists. The hallmark of prion disease... (Review)
Review
Prion diseases are neurodegenerative diseases that affect humans and animals. They are always fatal and, to date, no treatment exists. The hallmark of prion disease pathophysiology is the misfolding of an endogenous protein, the cellular prion protein (PrP), into its disease-associated isoform PrP. Besides the aggregation and deposition of misfolded PrP, prion diseases are characterized by spongiform lesions and the activation of astrocytes and microglia. Microglia are the innate immune cells of the brain. Activated microglia and astrocytes represent a common pathological feature in neurodegenerative disorders. The role of activated microglia has already been studied in prion disease mouse models; however, it is still not fully clear how they contribute to disease progression. Moreover, the role of microglia in human prion diseases has not been thoroughly investigated thus far, and specific molecular pathways are still undetermined. Here, we review the current knowledge on the different roles of microglia in prion pathophysiology. We discuss microglia markers that are also dysregulated in other neurodegenerative diseases including microglia homeostasis markers. Data on murine and human brain tissues show that microglia are highly dysregulated in prion diseases. We highlight here that the loss of homeostatic markers may especially stand out.
Topics: Animals; Homeostasis; Humans; Mice; Microglia; Neurodegenerative Diseases; Prion Diseases; Prion Proteins; Prions; Protein Isoforms
PubMed: 36230910
DOI: 10.3390/cells11192948 -
Open Veterinary Journal 2021Animal prion diseases are a group of neurodegenerative, transmissible, and fatal disorders that affect several animal species. The causative agent, prion, is a misfolded... (Review)
Review
Animal prion diseases are a group of neurodegenerative, transmissible, and fatal disorders that affect several animal species. The causative agent, prion, is a misfolded isoform of normal cellular prion protein, which is found in cells with higher concentration in the central nervous system. This review explored the sources of infection and different natural transmission routes of animal prion diseases in susceptible populations. Chronic wasting disease in cervids and scrapie in small ruminants are prion diseases capable of maintaining themselves in susceptible populations through horizontal and vertical transmission. The other prion animal diseases can only be transmitted through food contaminated with prions. Bovine spongiform encephalopathy (BSE) is the only animal prion disease considered zoonotic. However, due to its inability to transmit within a population, it could be controlled. The emergence of atypical cases of scrapie and BSE, even the recent report of prion disease in camels, demonstrates the importance of understanding the transmission routes of prion diseases to take measures to control them and to assess the risks to human and animal health.
Topics: Animals; Cattle; Cattle Diseases; Disease Susceptibility; Encephalopathy, Bovine Spongiform; Prion Diseases; Prions; Scrapie; Sheep; Sheep Diseases
PubMed: 35070868
DOI: 10.5455/OVJ.2021.v11.i4.23