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 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 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 Rapid and Sensitive RT-QuIC Detection of Human Creutzfeldt-Jakob Disease Using Cerebrospinal Fluid

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Christina D. Orrú ◽  
Bradley R. Groveman ◽  
Andrew G. Hughson ◽  
Gianluigi Zanusso ◽  
Michael B. Coulthart ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Analytical Sensitivity ◽  
Enhanced Sensitivity ◽  
Highly Sensitive ◽  
Jakob Disease ◽  
Misfolding Diseases ◽  
Amyloid Diseases ◽  
Sporadic Cjd

ABSTRACT  Fast, definitive diagnosis of Creutzfeldt-Jakob disease (CJD) is important in assessing patient care options and transmission risks. Real-time quaking-induced conversion (RT-QuIC) assays of cerebrospinal fluid (CSF) and nasal-brushing specimens are valuable in distinguishing CJD from non-CJD conditions but have required 2.5 to 5 days. Here, an improved RT-QuIC assay is described which identified positive CSF samples within 4 to 14 h with better analytical sensitivity. Moreover, analysis of 11 CJD patients demonstrated that while 7 were RT-QuIC positive using the previous conditions, 10 were positive using the new assay. In these and further analyses, a total of 46 of 48 CSF samples from sporadic CJD patients were positive, while all 39 non-CJD patients were negative, giving 95.8% diagnostic sensitivity and 100% specificity. This second-generation RT-QuIC assay markedly improved the speed and sensitivity of detecting prion seeds in CSF specimens from CJD patients. This should enhance prospects for rapid and accurate ante mortem CJD diagnosis. IMPORTANCE A long-standing problem in dealing with various neurodegenerative protein misfolding diseases is early and accurate diagnosis. This issue is particularly important with human prion diseases, such as CJD, because prions are deadly, transmissible, and unusually resistant to decontamination. The recently developed RT-QuIC test allows for highly sensitive and specific detection of CJD in human cerebrospinal fluid and is being broadly implemented as a key diagnostic tool. However, as currently applied, RT-QuIC takes 2.5 to 5 days and misses 11 to 23% of CJD cases. Now, we have markedly improved RT-QuIC analysis of human CSF such that CJD and non-CJD patients can be discriminated in a matter of hours rather than days with enhanced sensitivity. These improvements should allow for much faster, more accurate, and practical testing for CJD. In broader terms, our study provides a prototype for tests for misfolded protein aggregates that cause many important amyloid diseases, such as Alzheimer’s, Parkinson’s, and tauopathies.

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 PMCA Applications for Prion Detection in Peripheral Tissues of Patients with Variant Creutzfeldt-Jakob Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 405 ◽  
Author(s):  
Giorgio Giaccone ◽  
Fabio Moda
Keyword(s):  
Protein Misfolding ◽  
Prion Diseases ◽  
Disease Diagnosis ◽  
Diagnostic Techniques ◽  
Spongiform Encephalopathy ◽  
Variant Form ◽  
Definite Diagnosis ◽  
Peripheral Tissues ◽  
New Variant ◽  
Jakob Disease

Prion diseases are neurodegenerative and invariably fatal conditions that affect humans and animals. In particular, Creutzfeldt-Jakob disease (CJD) and bovine spongiform encephalopathy (BSE) are paradigmatic forms of human and animal prion diseases, respectively. Human exposure to BSE through contaminated food caused the appearance of the new variant form of CJD (vCJD). These diseases are caused by an abnormal prion protein named PrPSc (or prion), which accumulates in the brain and leads to the onset of the disease. Their definite diagnosis can be formulated only at post-mortem after biochemical and neuropathological identification of PrPSc. Thanks to the advent of an innovative technique named protein misfolding cyclic amplification (PMCA), traces of PrPSc, undetectable with the standard diagnostic techniques, were found in peripheral tissues of patients with vCJD, even at preclinical stages. The technology is currently being used in specialized laboratories and can be exploited for helping physicians in formulating an early and definite diagnosis of vCJD using peripheral tissues. However, this assay is currently unable to detect prions associated with the sporadic CJD (sCJD) forms, which are more frequent than vCJD. This review will focus on the most recent advances and applications of PMCA in the field of vCJD and other human prion disease diagnosis.

scholarly journals Decrease in Skin Prion-Seeding Activity of Prion-Infected Mice Treated with a Compound Against Human and Animal Prions: a First Possible Biomarker for Prion Therapeutics

2021 ◽  
Author(s):  
Mingxuan Ding ◽  
Kenta Teruya ◽  
Weiguanliu Zhang ◽  
Hae Weon Lee ◽  
Jue Yuan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Prion Protein ◽  
Therapeutic Efficacy ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Inhibitory Effect ◽  
Cellular Prion Protein ◽  
Cellulose Ethers ◽  
Wasting Disease

AbstractPrevious studies have revealed that the infectious scrapie isoform of prion protein (PrPSc) harbored in the skin tissue of patients or animals with prion diseases can be amplified and detected through the serial protein misfolding cyclic amplification (sPMCA) or real-time quaking-induced conversion (RT-QuIC) assays. These findings suggest that skin PrPSc-seeding activity may serve as a biomarker for the diagnosis of prion diseases; however, its utility as a biomarker for prion therapeutics remains largely unknown. Cellulose ethers (CEs, such as TC-5RW), widely used as food and pharmaceutical additives, have recently been shown to prolong the lifespan of prion-infected mice and hamsters. Here we report that in transgenic (Tg) mice expressing hamster cellular prion protein (PrPC) infected with the 263K prion, the prion-seeding activity becomes undetectable in the skin tissues of TC-5RW-treated Tg mice by both sPMCA and RT-QuIC assays, whereas such prion-seeding activity is readily detectable in the skin of untreated mice. Notably, TC-5RW exhibits an inhibitory effect on the in vitro amplification of PrPSc in both skin and brain tissues by sPMCA and RT-QuIC. Moreover, we reveal that TC-5RW is able to directly decrease protease-resistant PrPSc and inhibit the seeding activity of PrPSc from chronic wasting disease and various human prion diseases. Our results suggest that the level of prion-seeding activity in the skin may serve as a useful biomarker for assessing the therapeutic efficacy of compounds in a clinical trial of prion diseases and that TC-5RW may have the potential for the prevention/treatment of human prion diseases.

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.

scholarly journals Generation of human chronic wasting disease in transgenic mice

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Zerui Wang ◽  
Kefeng Qin ◽  
Manuel V. Camacho ◽  
Ignazio Cali ◽  
Jue Yuan ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Prion Disease ◽  
Protein Misfolding ◽  
Chronic Wasting Disease ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Species Barrier ◽  
Wasting Disease ◽  
Bona Fide

AbstractChronic wasting disease (CWD) is a cervid prion disease caused by the accumulation of an infectious misfolded conformer (PrPSc) of cellular prion protein (PrPC). It has been spreading rapidly in North America and also found in Asia and Europe. Although bovine spongiform encephalopathy (i.e. mad cow disease) is the only animal prion disease known to be zoonotic, the transmissibility of CWD to humans remains uncertain. Here we report the generation of the first CWD-derived infectious human PrPSc by elk CWD PrPSc-seeded conversion of PrPC in normal human brain homogenates using in vitro protein misfolding cyclic amplification (PMCA). Western blotting with human PrP selective antibody confirmed that the PMCA-generated protease-resistant PrPSc was derived from the human PrPC substrate. Two lines of humanized transgenic mice expressing human PrP with either Val or Met at the polymorphic codon 129 developed clinical prion disease following intracerebral inoculation with the PMCA-generated CWD-derived human PrPSc. Diseased mice exhibited distinct PrPSc patterns and neuropathological changes in the brain. Our study, using PMCA and animal bioassays, provides the first evidence that CWD PrPSc can cross the species barrier to convert human PrPC into infectious PrPSc that can produce bona fide prion disease when inoculated into humanized transgenic mice.

scholarly journals Characterization of mesenchymal stem cells in sheep naturally infected with scrapie

2015 ◽  
Vol 96 (12) ◽  
pp. 3715-3726 ◽  
Author(s):  
Diego R. Mediano ◽  
David Sanz-Rubio ◽  
Rosa Bolea ◽  
Belén Marín ◽  
Francisco J. Vázquez ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Transcript Level ◽  
Cellular Prion Protein ◽  
Jakob Disease

Mesenchymal stem cells (MSCs) can be infected with prions and have been proposed as in vitro cell-based models for prion replication. In addition, autologous MSCs are of interest for cell therapy in neurodegenerative diseases. To the best of our knowledge, the effect of prion diseases on the characteristics of these cells has never been investigated. Here, we analysed the properties of MSCs obtained from bone marrow (BM-MSCs) and peripheral blood (PB-MSCs) of sheep naturally infected with scrapie — a large mammal model for the study of prion diseases. After three passages of expansion, MSCs derived from scrapie animals displayed similar adipogenic, chondrogenic and osteogenic differentiation ability as cells from healthy controls, although a subtle decrease in the proliferation potential was observed. Exceptionally, mesenchymal markers such as CD29 were significantly upregulated at the transcript level compared with controls. Scrapie MSCs were able to transdifferentiate into neuron-like cells, but displayed lower levels of neurogenic markers at basal conditions, which could limit this potential. The expression levels of cellular prion protein (PrPC) were highly variable between cultures, and no significant differences were observed between control and scrapie-derived MSCs. However, during neurogenic differentiation the expression of PrPC was upregulated in MSCs. This characteristic could be useful for developing in vitro models for prion replication. Despite the infectivity reported for MSCs obtained from scrapie-infected mice and Creutzfeldt–Jakob disease patients, protein misfolding cyclic amplification did not detect PrPSc in BM- or PB-MSCs from scrapie-infected sheep, which limits their use for in vivo diagnosis for scrapie.

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.

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