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Pathogens
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Human Prion Disease
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Human Prion Disease

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Prions".

Deadline for manuscript submissions: closed (15 June 2022) | Viewed by 19861

Special Issue Editor

Prof. Dr. Pawel P. Liberski

E-Mail Website
Guest Editor
Laboratory of Electron Microscopy and Neuropathology, Department of Molecular Pathology and Neuropathology, Medical University Lodz, 90-419 Lodz, Poland
Interests: neurodegenerative diseases; Alzheimer's disease; neurological diseases

Special Issue Information

Prion diseases are a unique class of neurodegenerations caused by prions. Prions are abnormally folded proteins which originate from normal cellular proteins. For instance, in scrapie, normal protein (PrPc) is encoded by a cellur gene while abnormal protein (PrPSc) is an apathohenic one. Several other proteins like Ab in Alzheimer disease or a-synuclein in Parkinson disease and multiple system atrophy behave like prions. Prions are encountered not only in humans and animals but also in yeasts.

This Special Issue aims to highlight recent advances in the prion field. Both reviews and original articles are welcome. 

Topics can include but are not limited to: 

  1. Neuropathology of prion disease
  2. The nature of prions
  3. Structural biology of prions
  4. Mechanisms of prion diseases 

Prof. Dr. Pawel Liberski
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (6 papers)

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Research

Jump to: Review

11 pages, 1670 KiB  
Article
Experimental Bovine Spongiform Encephalopathy in Squirrel Monkeys: The Same Complex Proteinopathy Appearing after Very Different Incubation Times
by Pedro Piccardo, Juraj Cervenak, Wilfred Goldmann, Paula Stewart, Kitty L. Pomeroy, Luisa Gregori, Oksana Yakovleva and David M. Asher
Pathogens 2022, 11(5), 597; https://doi.org/10.3390/pathogens11050597 - 20 May 2022
Viewed by 2779
Abstract
Incubation periods in humans infected with transmissible spongiform encephalopathy (TSE) agents can exceed 50 years. In humans infected with bovine spongiform encephalopathy (BSE) agents, the effects of a “species barrier,” often observed when TSE infections are transmitted from one species to another, would [...] Read more.
Incubation periods in humans infected with transmissible spongiform encephalopathy (TSE) agents can exceed 50 years. In humans infected with bovine spongiform encephalopathy (BSE) agents, the effects of a “species barrier,” often observed when TSE infections are transmitted from one species to another, would be expected to increase incubation periods compared with transmissions of same infectious agents within the same species. As part of a long-term study investigating the susceptibility to BSE of cell cultures used to produce vaccines, we inoculated squirrel monkeys (Saimiri sp., here designated SQ) with serial dilutions of a bovine brain suspension containing the BSE agent and monitored them for as long as ten years. Previously, we showed that SQ infected with the original “classical” BSE agent (SQ-BSE) developed a neurological disease resembling that seen in humans with variant CJD (vCJD). Here, we report the final characterization of the SQ-BSE model. We observed an unexpectedly marked difference in incubation times between two animals inoculated with the same dilution and volume of the same C-BSE bovine brain extract on the same day. SQ-BSE developed, in addition to spongiform changes and astrogliosis typical of TSEs, a complex proteinopathy with severe accumulations of protease-resistant prion protein (PrPTSE), hyperphosphorylated tau (p-tau), ubiquitin, and α-synuclein, but without any amyloid plaques or β-amyloid protein (Aβ) typical of Alzheimer’s disease. These results suggest that PrPTSE enhanced the accumulation of several key proteins characteristically seen in human neurodegenerative diseases. The marked variation in incubation periods in the same experimental TSE should be taken into account when modeling the epidemiology of human TSEs. Full article
(This article belongs to the Special Issue Human Prion Disease)
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9 pages, 1560 KiB  
Article
Defining the Prion Type of Fatal Familial Insomnia
by Wiebke Jürgens-Wemheuer, Arne Wrede and Walter Schulz-Schaeffer
Pathogens 2021, 10(10), 1293; https://doi.org/10.3390/pathogens10101293 - 7 Oct 2021
Cited by 2 | Viewed by 3292
Abstract
Fatal familial insomnia (FFI) belongs to the genetic human transmissible spongiform encephalopathies (TSE), such as genetic Creutzfeldt-Jakob disease (CJD) or Gerstmann-Straeussler-Scheinker syndrome (GSS). Here, we analyzed the properties of the pathological prion protein in six FFI cases by Western blot analysis, a protein [...] Read more.
Fatal familial insomnia (FFI) belongs to the genetic human transmissible spongiform encephalopathies (TSE), such as genetic Creutzfeldt-Jakob disease (CJD) or Gerstmann-Straeussler-Scheinker syndrome (GSS). Here, we analyzed the properties of the pathological prion protein in six FFI cases by Western blot analysis, a protein aggregate stability assay, and aggregate deposition characteristics visualized with the paraffin-embedded tissue blot. While in all cases the unglycosylated fragment in Western blot analysis shared the same size with sporadic CJD prion type 2, the reticular/synaptic deposition pattern of the prion aggregates resembled the ones found in sporadic CJD type 1 (CJD types according to the Parchi classification from 1999). Regarding the conformational stability against denaturation with GdnHCl, FFI prion aggregates resembled CJD type 1 more than type 2. Our results suggest that the size of the proteinase-K-resistant fragments is not a valid criterion on its own. Additional criteria supplying information about conformational differences or similarities need to be taken into account. FFI may resemble a prion type with its own conformation sharing properties partly with type 1 and type 2 prions. Full article
(This article belongs to the Special Issue Human Prion Disease)
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8 pages, 694 KiB  
Communication
Propagation of CJD Prions in Primary Murine Glia Cells Expressing Human PrPc
by Joo-Hee Wälzlein, Karla A. Schwenke and Michael Beekes
Pathogens 2021, 10(8), 1060; https://doi.org/10.3390/pathogens10081060 - 20 Aug 2021
Cited by 6 | Viewed by 2449
Abstract
There are various existing cell models for the propagation of animal prions. However, in vitro propagation of human prions has been a long-standing challenge. This study presents the establishment of a long-term primary murine glia culture expressing the human prion protein homozygous for [...] Read more.
There are various existing cell models for the propagation of animal prions. However, in vitro propagation of human prions has been a long-standing challenge. This study presents the establishment of a long-term primary murine glia culture expressing the human prion protein homozygous for methionine at codon 129, which allows in vitro propagation of Creutzfeldt–Jakob disease (CJD) prions (variant CJD (vCJD) and sporadic CJD (sCJD) type MM2). Prion propagation could be detected by Western blotting of pathological proteinase K-resistant prion protein (PrPSc) from 120 days post exposure. The accumulation of PrPSc could be intensified by adding a cationic lipid mixture to the infectious brain homogenate at the time of infection. Stable propagation of human prions in a long-term murine glia cell culture represents a new tool for future drug development and for mechanistic studies in the field of human prion biology. In addition, our cell model can reduce the need for bioassays with human prions and thereby contributes to further implementation of the 3R principles aiming at replacement, reduction and refinement of animal experiments. Full article
(This article belongs to the Special Issue Human Prion Disease)
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16 pages, 6096 KiB  
Article
Novel Morphological Glial Alterations in the Spectrum of Prion Disease Types: A Focus on Common Findings
by Moisés Garcés, Isabel M. Guijarro, Diane L. Ritchie, Juan J. Badiola and Marta Monzón
Pathogens 2021, 10(5), 596; https://doi.org/10.3390/pathogens10050596 - 13 May 2021
Cited by 2 | Viewed by 2617
Abstract
Human prion diseases are a group of rare fatal neurodegenerative diseases with sporadic, genetic, and acquired forms. They are neuropathologically characterized by pathological prion protein accumulation, neuronal death, and vacuolation. Classical immunological response has long been known not to play a major in [...] Read more.
Human prion diseases are a group of rare fatal neurodegenerative diseases with sporadic, genetic, and acquired forms. They are neuropathologically characterized by pathological prion protein accumulation, neuronal death, and vacuolation. Classical immunological response has long been known not to play a major in prion diseases; however, gliosis is known to be a common feature although variable in extent and poorly described. In this investigation, astrogliosis and activated microglia in two brain regions were assessed and compared with non-neurologically affected patients in a representative sample across the spectrum of Creutzfeldt–Jakob disease (CJD) forms and subtypes in order to analyze the influence of prion strain on pathological processes. In this report, we choose to focus on features common to all CJD types rather than the diversity among them. Novel pathological changes in both glial cell types were found to be shared by all CJD types. Microglial activation correlated to astrogliosis. Spongiosis, but not pathological prion protein deposition, correlated to both astrogliosis and microgliosis. At the ultrastructural level, astrocytic glial filaments correlated with pathological changes associated with prion disease. These observations confirm that neuroglia play a prominent role in the neurodegenerative process of prion diseases, regardless of the causative prion type. Full article
(This article belongs to the Special Issue Human Prion Disease)
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5 pages, 396 KiB  
Article
Genetic Risk Factors of Creutzfeldt-Jakob Disease in the Population of Newborns in Slovakia
by Dana Kosorinova, Girma Belay, Dana Zakova, Martin Stelzer and Eva Mitrova
Pathogens 2021, 10(4), 435; https://doi.org/10.3390/pathogens10040435 - 6 Apr 2021
Cited by 6 | Viewed by 2474
Abstract
The most frequent human prion disease is Creutzfeldt–Jakob disease (CJD). It occurs as sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD) form and as variant CJD. The genetic form represents about 10–15% of confirmed cases worldwide, in Slovakia as much as 65–75%. Focal accumulation of [...] Read more.
The most frequent human prion disease is Creutzfeldt–Jakob disease (CJD). It occurs as sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD) form and as variant CJD. The genetic form represents about 10–15% of confirmed cases worldwide, in Slovakia as much as 65–75%. Focal accumulation of gCJD was confirmed in Orava region. The most common point mutation of the prion protein gene (PRNP) is E200K. CJD has a long asymptomatic phase and it is not known when the carriers of the mutation E200K become infectious. Precautions to prevent iCJD are focused especially on clinical CJD cases, but asymptomatic CJD-specific mutation carriers cannot be excluded, and represent a potential genetic CJD-risk group. The aim of this study was to determine the occurrence, frequency and geographic distribution of the E200K mutation among the newborns, comparing the areas of focal accumulation of gCJD with extra-focal ones, as well as distribution of the polymorphism M129V of the PRNP gene. A total of 2915 samples of dry blood spots from anonymous newborns were analyzed. We used RealTime PCR method to determine the presence of the E200K mutation and the M129V polymorphism. Genetic testing revealed 13 carriers of the E200K mutation. Investigation of the M129V polymorphism affirmed higher representation of methionine homozygotes (48% MM, 44% MV, 8% VV). Achieved results fully confirmed our previous observations concerning both the specific and nonspecific genetic CJD risk among the Slovak general population. The 48% of methionine homozygotes and 4 carriers of the E200K mutation among 1000 live-born children in Slovakia underline the benefits of genetic testing. Full article
(This article belongs to the Special Issue Human Prion Disease)
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Review

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20 pages, 2884 KiB  
Review
Variant CJD: Reflections a Quarter of a Century on
by Diane L. Ritchie, Alexander H. Peden and Marcelo A. Barria
Pathogens 2021, 10(11), 1413; https://doi.org/10.3390/pathogens10111413 - 30 Oct 2021
Cited by 19 | Viewed by 5031
Abstract
Twenty-five years has now passed since variant Creutzfeldt-Jakob disease (vCJD) was first described in the United Kingdom (UK). Early epidemiological, neuropathological and biochemical investigations suggested that vCJD represented a new zoonotic form of human prion disease resulting from dietary exposure to the bovine [...] Read more.
Twenty-five years has now passed since variant Creutzfeldt-Jakob disease (vCJD) was first described in the United Kingdom (UK). Early epidemiological, neuropathological and biochemical investigations suggested that vCJD represented a new zoonotic form of human prion disease resulting from dietary exposure to the bovine spongiform encephalopathy (BSE) agent. This hypothesis has since been confirmed though a large body of experimental evidence, predominantly using animal models of the disease. Today, the clinical, pathological and biochemical phenotype of vCJD is well characterized and demonstrates a unique and remarkably consistent pattern between individual cases when compared to other human prion diseases. While the numbers of vCJD cases remain reassuringly low, with 178 primary vCJD cases reported in the UK and a further 54 reported worldwide, concerns remain over the possible appearance of new vCJD cases in other genetic cohorts and the numbers of asymptomatic individuals in the population harboring vCJD infectivity. This review will provide a historical perspective on vCJD, examining the origins of this acquired prion disease and its association with BSE. We will investigate the epidemiology of the disease along with the unique clinicopathological and biochemical phenotype associated with vCJD cases. Additionally, this review will examine the impact vCJD has had on public health in the UK and the ongoing concerns raised by this rare group of disorders. Full article
(This article belongs to the Special Issue Human Prion Disease)
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