scholarly journals From Prion Diseases to Prion-Like Propagation Mechanisms of Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Isabelle Acquatella-Tran Van Ba ◽  
Thibaut Imberdis ◽  
Véronique Perrier
Keyword(s):  
Neurodegenerative Disorders ◽  
Small Rnas ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Original Works ◽  
Jakob Disease ◽  
The Brain ◽  
Prion Hypothesis

Prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. In humans, Creutzfeldt-Jakob disease is the most studied prion disease. In animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in North America. The hallmark of prion diseases is the deposition in the brain of PrPSc, an abnormalβ-sheet-rich form of the cellular prion protein (PrPC) (Prusiner 1982). According to the prion hypothesis, PrPSccan trigger the autocatalytic conversion of PrPCinto PrPSc, presumably in the presence of cofactors (lipids and small RNAs) that have been recently identified. In this review, we will come back to the original works that led to the discovery of prions and to the protein-only hypothesis proposed by Dr. Prusiner. We will then describe the recent reports on mammalian synthetic prions and recombinant prions that strongly support the protein-only hypothesis. The new concept of “deformed templating” regarding a new mechanism of PrPScformation and replication will be exposed. The review will end with a chapter on the prion-like propagation of other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease and tauopathies.

scholarly journals Small-Molecule Theranostic Probes: A Promising Future in Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-19 ◽  
Author(s):  
Suzana Aulić ◽  
Maria Laura Bolognesi ◽  
Giuseppe Legname
Keyword(s):  
Protein Misfolding ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Infectious Agents ◽  
Wasting Disease ◽  
Imaging Probes ◽  
Jakob Disease ◽  
Misfolding Diseases ◽  
Practical Implications

Prion diseases are fatal neurodegenerative illnesses, which include Creutzfeldt-Jakob disease in humans and scrapie, chronic wasting disease, and bovine spongiform encephalopathy in animals. They are caused by unconventional infectious agents consisting primarily of misfolded, aggregated,β-sheet-rich isoforms, denoted prions, of the physiological cellular prion protein (PrPC). Many lines of evidence suggest that prions (PrPSc) act both as a template for this conversion and as a neurotoxic agent causing neuronal dysfunction and cell death. As such,PrPScmay be considered as both a neuropathological hallmark of the disease and a therapeutic target. Several diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders (such as Alzheimer’s disease, Parkinson’s disease, and prion disease). Examples of these probes are Congo red, thioflavin T, and their derivatives. We synthesized a series of styryl derivatives, denoted theranostics, and studied their therapeutic and/or diagnostic potentials. Here we review the salient traits of these small molecules that are able to detect and modulate aggregated forms of several proteins involved in protein misfolding diseases. We then highlight the importance of further studies for their practical implications in therapy and diagnostics.

scholarly journals Prions: Some Details and Diseases

2021 ◽  
Vol 2 (3) ◽  
pp. 80-94
Author(s):  
Saif Jabbar Yasir ◽  
Taghreed Abdul Kareem Al- Makhzoomy
Keyword(s):  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Spongiform Encephalopathies ◽  
Incubation Periods ◽  
Jakob Disease

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of rare progressive neurodegenerative disorders that affect both humans and animals. They are distinguished by long incubation periods, characteristic spongiform changes associated with neuronal loss, and a failure to induce inflammatory response. Prion diseases in animals, Scrapie in sheep, chronic wasting disease (CWD) in deer, bovine spongiform encephalopathy (commonly known as "mad cow disease") in cattle, and Creutzfeldt-Jakob disease in humans are all examples of infectious diseases. The prion protein (PrP) was identified in a patient in 2015, and it was previously believed to be the cause of all known mammalian prion diseases. However, The protein alpha-synuclein, which is thought to be responsible for MSA, was suggested to be the cause of the disease in 2015.

scholarly journals Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91–106

2020 ◽  
Vol 21 (19) ◽  
pp. 7260
Author(s):  
Keiji Uchiyama ◽  
Hironori Miyata ◽  
Yoshitaka Yamaguchi ◽  
Morikazu Imamura ◽  
Mariya Okazaki ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Dependent Manner ◽  
Prion Infection ◽  
Amplification Assay ◽  
The Brain ◽  
Strain Dependent

Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform, PrPSc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91–106 were generated in the absence of endogenous PrPC, designated Tg(PrP∆91–106)/Prnp0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91–106)/Prnp0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrPSc∆91–106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrPSc∆91–106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrPSc∆91–104 after incubation with BSE-PrPSc-prions but not with RML- and 22L–PrPSc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91–104 into PrPSc∆91–104 even after incubation with RML- and 22L-PrPSc-prions. These results suggest that residues 91–106 or 91–104 of PrPC are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc.

scholarly journals Vaccination with Prion Peptide-Displaying Polyomavirus-Like Particles Prolongs Incubation Time in Scrapie-Infected Mice

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 811
Author(s):  
Martin Eiden ◽  
Alma Gedvilaite ◽  
Fabienne Leidel ◽  
Rainer G. Ulrich ◽  
Martin H. Groschup
Keyword(s):  
Prion Diseases ◽  
Mammalian Species ◽  
Cellular Prion Protein ◽  
Control Group ◽  
Spongiform Encephalopathy ◽  
Post Inoculation ◽  
Self Tolerance ◽  
Jakob Disease ◽  
Capsid Protein Vp1 ◽  
Conformational Conversion

Prion diseases like scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle or Creutzfeldt–Jakob disease (CJD) in humans are fatal neurodegenerative diseases characterized by the conformational conversion of the normal, mainly α-helical cellular prion protein (PrPC) into the abnormal β-sheet rich infectious isoform PrPSc. Various therapeutic or prophylactic approaches have been conducted, but no approved therapeutic treatment is available so far. Immunisation against prions is hampered by the self-tolerance to PrPC in mammalian species. One strategy to avoid this tolerance is presenting PrP variants in virus-like particles (VLPs). Therefore, we vaccinated C57/BL6 mice with nine prion peptide variants presented by hamster polyomavirus capsid protein VP1/VP2-derived VLPs. Mice were subsequently challenged intraperitoneally with the murine RML prion strain. Importantly, one group exhibited significantly increased mean survival time of 240 days post-inoculation compared with 202 days of the control group. These data show that immunisation with VLPs presenting PrP peptides may represent a promising strategy for an effective vaccination against transmissible spongiform encephalitis agents.

Genetic Factors in Mammalian Prion Diseases

2019 ◽  
Vol 53 (1) ◽  
pp. 117-147 ◽  
Author(s):  
Simon Mead ◽  
Sarah Lloyd ◽  
John Collinge
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Protein Interactions ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Cellular Functions ◽  
Modifying Factors ◽  
Jakob Disease ◽  
The Central Nervous System

Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; kuru; inherited prion disease; sheep scrapie; bovine spongiform encephalopathy; and chronic wasting disease. Prions are composed of misfolded and multimeric forms of the normal cellular prion protein (PrP). Prion diseases require host expression of the prion protein gene ( PRNP) and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of PRNP, whereas acquired and sporadically occurring mammalian prion diseases are controlled by powerful genetic risk and modifying factors. Whereas some PrP amino acid variants cause the disease, others confer protection, dramatically altered incubation times, or changes in the clinical phenotype. Multiple mechanisms, including interference with homotypic protein interactions and the selection of the permissible prion strains in a host, play a role. Several non- PRNP factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.

scholarly journals Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Tahir Ali ◽  
Samia Hannaoui ◽  
Satish Nemani ◽  
Waqas Tahir ◽  
Irina Zemlyankina ◽  
...  
Keyword(s):  
Oral Administration ◽  
Prion Diseases ◽  
Neuronal Cells ◽  
Cellular Prion Protein ◽  
Disease Stage ◽  
Survival Times ◽  
Valuable Treatment ◽  
Advanced Disease Stage ◽  
Jakob Disease ◽  
The Brain

AbstractPrion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform (PrPSc). In humans, there are sporadic, genetic and infectious etiologies, with sporadic Creutzfeldt-Jakob disease (sCJD) being the most common form. Currently, no treatment is available for prion diseases. Cellular cholesterol is known to impact prion conversion, which in turn results in an accumulation of cholesterol in prion-infected neurons. The major elimination of brain cholesterol is achieved by the brain specific enzyme, cholesterol 24-hydroxylase (CYP46A1). Cyp46A1 converts cholesterol into 24(S)-hydroxycholesterol, a membrane-permeable molecule that exits the brain. We have demonstrated for the first time that Cyp46A1 levels are reduced in the brains of prion-infected mice at advanced disease stage, in prion-infected neuronal cells and in post-mortem brains of sCJD patients. We have employed the Cyp46A1 activator efavirenz (EFV) for treatment of prion-infected neuronal cells and mice. EFV is an FDA approved anti-HIV medication effectively crossing the blood brain barrier and has been used for decades to chronically treat HIV patients. EFV significantly mitigated PrPSc propagation in prion-infected cells while preserving physiological PrPC and lipid raft integrity. Notably, oral administration of EFV treatment chronically at very low dosage starting weeks to months after intracerebral prion inoculation of mice significantly prolonged the lifespan of animals. In summary, our results suggest that Cyp46A1 as a novel therapeutic target and that its activation through repurposing the anti-retroviral medication EFV might be valuable treatment approach for prion diseases.

scholarly journals Mechanisms of prion-induced neurodegeneration

2016 ◽  
Vol 18 ◽  
Author(s):  
Paula Saá ◽  
David A. Harris ◽  
Larisa Cervenakova
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Therapeutic Approaches ◽  
Spongiform Encephalopathies ◽  
Membrane Bound ◽  
The Brain

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurodegenerative disorders characterised by long incubation period, short clinical duration, and transmissibility to susceptible species. Neuronal loss, spongiform changes, gliosis and the accumulation in the brain of the misfolded version of a membrane-bound cellular prion protein (PrPC), termed PrPTSE, are diagnostic markers of these diseases. Compelling evidence links protein misfolding and its accumulation with neurodegenerative changes. Accordingly, several mechanisms of prion-mediated neurotoxicity have been proposed. In this paper, we provide an overview of the recent knowledge on the mechanisms of neuropathogenesis, the neurotoxic PrP species and the possible therapeutic approaches to treat these devastating disorders.

scholarly journals Porcine Prion Protein as a Paradigm of Limited Susceptibility to Prion Strain Propagation

2020 ◽  
Author(s):  
Juan Carlos Espinosa ◽  
Alba Marín-Moreno ◽  
Patricia Aguilar-Calvo ◽  
Sylvie L Benestad ◽  
Olivier Andreoletti ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Conformational Flexibility ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Prion Strain ◽  
Experimental Transmission ◽  
Prion Strains ◽  
Jakob Disease

Abstract Although experimental transmission of bovine spongiform encephalopathy (BSE) to pigs and transgenic mice expressing pig cellular prion protein (PrPC) (porcine PrP [PoPrP]–Tg001) has been described, no natural cases of prion diseases in pig were reported. This study analyzed pig-PrPC susceptibility to different prion strains using PoPrP-Tg001 mice either as animal bioassay or as substrate for protein misfolding cyclic amplification (PMCA). A panel of isolates representatives of different prion strains was selected, including classic and atypical/Nor98 scrapie, atypical-BSE, rodent scrapie, human Creutzfeldt-Jakob-disease and classic BSE from different species. Bioassay proved that PoPrP-Tg001-mice were susceptible only to the classic BSE agent, and PMCA results indicate that only classic BSE can convert pig-PrPC into scrapie-type PrP (PrPSc), independently of the species origin. Therefore, conformational flexibility constraints associated with pig-PrP would limit the number of permissible PrPSc conformations compatible with pig-PrPC, thus suggesting that pig-PrPC may constitute a paradigm of low conformational flexibility that could confer high resistance to the diversity of prion strains.

scholarly journals Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin

2008 ◽  
Vol 416 (2) ◽  
pp. 297-305 ◽  
Author(s):  
Sabrina Cronier ◽  
Nathalie Gros ◽  
M. Howard Tattum ◽  
Graham S. Jackson ◽  
Anthony R. Clarke ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Rocky Mountain ◽  
Proteinase K ◽  
Spongiform Encephalopathy ◽  
Prion Strains ◽  
Human Counterpart ◽  
Jakob Disease ◽  
The Brain

Disease-related PrPSc [pathogenic PrP (prion protein)] is classically distinguished from its normal cellular precursor, PrPC(cellular PrP) by its detergent insolubility and partial resistance to proteolysis. Although molecular diagnosis of prion disease has historically relied upon detection of protease-resistant fragments of PrPSc using PK (proteinase K), it is now apparent that a substantial fraction of disease-related PrP is destroyed by this protease. Recently, thermolysin has been identified as a complementary tool to PK, permitting isolation of PrPSc in its full-length form. In the present study, we show that thermolysin can degrade PrPC while preserving both PK-sensitive and PK-resistant isoforms of disease-related PrP in both rodent and human prion strains. For mouse RML (Rocky Mountain Laboratory) prions, the majority of PK-sensitive disease-related PrP isoforms do not appear to contribute significantly to infectivity. In vCJD (variant Creutzfeldt–Jakob disease), the human counterpart of BSE (bovine spongiform encephalopathy), up to 90% of total PrP present in the brain resists degradation with thermolysin, whereas only ∼15% of this material resists digestion by PK. Detection of PK-sensitive isoforms of disease-related PrP using thermolysin should be useful for improving diagnostic sensitivity in human prion diseases.

PRÍONS E DOENÇAS PRIÔNICAS: UMA REVISÃO

2020 ◽  
Vol 12 (2) ◽  
pp. 47-58
Author(s):  
Vinicio Berti
Keyword(s):  
Systematic Review ◽  
Bovine Spongiform Encephalopathy ◽  
Neurodegenerative Disorders ◽  
Spongiform Encephalopathy ◽  
General View ◽  
Chain Reaction ◽  
Wasting Disease ◽  
Jakob Disease ◽  
Altered Form ◽  
Sheep Scrapie

The name príon is given to an altered form of a protein present at the surface of neurons. Prions are remarkable for been able to induct their normal counterpart to assume the pathological configuration on a kind of chain reaction, with the possibility of trasmission between subjects and even through different species. Prions can cause a series of neurodegenerative disorders affecting humans (Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, kuru), and animals such cattle (bovine spongiform encephalopathy or “mad cow disease”), deer (chronic wasting disease) and sheep (scrapie). This article is a non-systematic review, obtained on PubMed, SciELO and Google Scholar databases, with the aim to give a general view about the nature of prions, followed by a brief discussion of the human diseases caused by prions.

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