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Cells
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Pathogenesis of Prion Diseases
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Pathogenesis of Prion Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 5019

Special Issue Editor

Prof. Dr. Ilia V. Baskakov

E-Mail Website
Guest Editor
Center for Biomedical Engineering and Technology, Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
Interests: prion diseases; neurodegenerative diseases; reactive microglia; reactive astrocytes

Special Issue Information

Dear Colleagues,

Prion diseases encompass a group of fatal neurodegenerative disorders affecting both humans and animals. They can arise spontaneously, through transmission, or as a result of familial mutations. The transmissible agent responsible for prion disease, known as PrPSc, comprises a prion protein existing in self-propagating states rich in β-sheets, which act as templates for converting the cellular form of the same protein (referred to as PrPC). In the disease-associated states, the prion protein gives rise to various disease phenotypes, which have been attributed to its ability to adopt multiple, structurally distinct states known as prion strains.

This Special Issue aims to bring together experts in the field of prion diseases to contribute original research articles, review articles, or perspectives on various aspects of prion diseases. Topics of interest include, but are not limited to:

  • Disease pathogenesis: investigating the underlying mechanisms and factors influencing the development and progression of prion diseases.
  • Mechanisms of prion toxicity: exploring the molecular mechanisms by which PrPSc exerts its detrimental effects on neuronal cells and brain tissue.
  • Neuroinflammation and the role of reactive microglia and astrocytes: investigating the involvement of neuroinflammation and the contributions of reactive microglia and astrocytes to the pathogenesis of prion diseases.
  • Prion transmission and transmission barriers: understanding the routes and modes of transmission of prion diseases in both humans and animals, as well as investigating the factors that dictate the transmission barriers.
  • Protein structure and co-factors: characterizing the structural features of PrPSc along with co-factors and metal ions that affect prion protein conformation and replication.
  • Prion strains and their evolution: elucidating the origin, diversity, and evolution of prion strains and their impact on disease phenotype.
  • Prion–host interactions: examining the interplay between prions and host factors, including cellular and molecular mechanisms involved in disease susceptibility and resistance.
  • Post-translational modifications: exploring the role of post-translational modifications in prion pathogenesis and strain diversity.
  • Diagnostic techniques: advancements in diagnostic tools and methods for detecting prion diseases.
  • Novel animal, cellular, and organoid models: developing and utilizing innovative models to study prion diseases and investigate therapeutic approaches.
  • Therapeutic targets: identifying potential therapeutic targets for the treatment and management of prion diseases.
  • Biological activities of PrPC: investigating functions and biological activities of PrPC in various cell types and tissues.

Prof. Dr. Ilia V. Baskakov
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. Cells is an international peer-reviewed open access semimonthly 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 2700 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.

Keywords

  • prions
  • prion diseases
  • Creutzfeldt–Jakob disease
  • neurodegenerative diseases
  • prion strains
  • species barrier
  • neuroinflammation
  • reactive microglia
  • reactive astrocytes
  • glycosylation

Published Papers (4 papers)

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Research

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22 pages, 4173 KiB  
Article
Region-Specific Homeostatic Identity of Astrocytes Is Essential for Defining Their Response to Pathological Insults
by Natallia Makarava, Olga Mychko, Kara Molesworth, Jennifer Chen-Yu Chang, Rebecca J. Henry, Natalya Tsymbalyuk, Volodymyr Gerzanich, J. Marc Simard, David J. Loane and Ilia V. Baskakov
Cells 2023, 12(17), 2172; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12172172 - 30 Aug 2023
Cited by 4 | Viewed by 1402
Abstract
The transformation of astrocytes into reactive states constitutes a biological response of the central nervous system under a variety of pathological insults. Astrocytes display diverse homeostatic identities that are developmentally predetermined and regionally specified. Upon transformation into reactive states associated with neurodegenerative diseases [...] Read more.
The transformation of astrocytes into reactive states constitutes a biological response of the central nervous system under a variety of pathological insults. Astrocytes display diverse homeostatic identities that are developmentally predetermined and regionally specified. Upon transformation into reactive states associated with neurodegenerative diseases and other neurological disorders, astrocytes acquire diverse reactive phenotypes. However, it is not clear whether their reactive phenotypes are dictated by region-specific homeostatic identity or by the nature of an insult. To address this question, region-specific gene expression profiling was performed for four brain regions (cortex, hippocampus, thalamus, and hypothalamus) in mice using a custom NanoString panel consisting of selected sets of genes associated with astrocyte functions and their reactivity for five conditions: prion disease, traumatic brain injury, brain ischemia, 5XFAD Alzheimer’s disease model and normal aging. Upon transformation into reactive states, genes that are predominantly associated with astrocytes were found to respond to insults in a region-specific manner. Regardless of the nature of the insult or the insult-specificity of astrocyte response, strong correlations between undirected GSA (gene set analysis) scores reporting on astrocyte reactivity and on their homeostatic functions were observed within each individual brain region. The insult-specific gene expression signatures did not separate well from each other and instead partially overlapped, forming continuums. The current study demonstrates that region-specific homeostatic identities of astrocytes are important for defining their response to pathological insults. Within region-specific populations, reactive astrocytes show continuums of gene expression signatures, partially overlapping between individual insults. Full article
(This article belongs to the Special Issue Pathogenesis of Prion Diseases)
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11 pages, 2544 KiB  
Article
Genetic Variants Associated with the Age of Onset Identified by Whole-Exome Sequencing in Fatal Familial Insomnia
by Katrin Thüne, Matthias Schmitz, John Wiedenhöft, Orr Shomroni, Stefan Göbel, Timothy Bunck, Neelam Younas, Saima Zafar, Peter Hermann and Inga Zerr
Cells 2023, 12(16), 2053; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12162053 - 12 Aug 2023
Viewed by 1158
Abstract
Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease with a wide variability in age of onset. Its causes are not known. In the present study, we aimed to analyze genetic risk factors other than the prion protein gene (PRNP [...] Read more.
Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease with a wide variability in age of onset. Its causes are not known. In the present study, we aimed to analyze genetic risk factors other than the prion protein gene (PRNP), in FFI patients with varying ages of onset. Whole-exome sequencing (WES) analysis was performed for twenty-five individuals with FFI (D178N-129M). Gene ontology enrichment analysis was carried out by Reactome to generate hypotheses regarding the biological processes of the identified genes. In the present study, we used a statistical approach tailored to the specifics of the data and identified nineteen potential gene variants with a potential effect on the age of onset. Evidence for potential disease modulatory risk loci was observed in two pseudogenes (NR1H5P, GNA13P1) and three protein coding genes (EXOC1L, SRSF11 and MSANTD3). These genetic variants are absent in FFI patients with early disease onset (19–40 years). The biological function of these genes and PRNP is associated with programmed cell death, caspase-mediated cleavage of cytoskeletal proteins and apoptotic cleavage of cellular proteins. In conclusions, our study provided first evidence for the involvement of genetic risk factors additional to PRNP, which may influence the onset of clinical symptoms in FFI. Full article
(This article belongs to the Special Issue Pathogenesis of Prion Diseases)
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18 pages, 5593 KiB  
Article
Innate Immune Status of Glia Modulates Prion Propagation in Early Stage of Infection
by Sang-Gyun Kang, Chiye Kim, Judd Aiken and Debbie McKenzie
Cells 2023, 12(14), 1878; https://doi.org/10.3390/cells12141878 - 18 Jul 2023
Cited by 1 | Viewed by 1348
Abstract
Prion diseases are progressive neurodegenerative disorders affecting humans and various mammals. The prominent neuropathological change in prion-affected brains is neuroinflammation, histopathologically characterized by reactive gliosis surrounding prion deposition. The cause and effect of these cellular responses are still unclear. Here we investigate the [...] Read more.
Prion diseases are progressive neurodegenerative disorders affecting humans and various mammals. The prominent neuropathological change in prion-affected brains is neuroinflammation, histopathologically characterized by reactive gliosis surrounding prion deposition. The cause and effect of these cellular responses are still unclear. Here we investigate the impact of innate immune responses on prion replication using in vitro cell culture models. Hamster-adapted transmissible mink encephalopathy prions, hyper (HY) and drowsy (DY) strains, were assayed for accumulation of pathogenic prion protein (PrPSc) in primary glial cultures derived from 8-day-old hamster pups. The kinetics of PrPSc accumulation largely depended on prion strain and brain regions from where glial cells originated. Glial cells derived from the cerebellum were susceptible to HY, but resistant to DY strain as determined by western blot analysis, immunocytochemistry, and animal bioassay. Glial cells from the cerebral cortex were, however, refractory to both strains. PrPSc accumulation was affected by innate immune modulators. Priming glial cells with lipopolysaccharide decreased prion replication, whereas pre-treatment with dexamethasone, inhibiting innate immunity, increased susceptibility to DY infection. Our results suggest that neuroinflammation resulting from prion infection is a response to resolve and/or prevent prion propagation in the brain. It implies a therapeutic potential of innate immune modulation in the early stages of prion disease. Full article
(This article belongs to the Special Issue Pathogenesis of Prion Diseases)
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Review

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15 pages, 784 KiB  
Review
The Role of Glial Cells in Neurobiology and Prion Neuropathology
by Arielle Hay, Katriana Popichak, Julie Moreno and Mark Zabel
Cells 2024, 13(10), 832; https://0-doi-org.brum.beds.ac.uk/10.3390/cells13100832 - 14 May 2024
Viewed by 661
Abstract
Prion diseases are rare and neurodegenerative diseases that are characterized by the misfolding and infectious spread of the prion protein in the brain, causing progressive and irreversible neuronal loss and associated clinical and behavioral manifestations in humans and animals, ultimately leading to death. [...] Read more.
Prion diseases are rare and neurodegenerative diseases that are characterized by the misfolding and infectious spread of the prion protein in the brain, causing progressive and irreversible neuronal loss and associated clinical and behavioral manifestations in humans and animals, ultimately leading to death. The brain has a complex network of neurons and glial cells whose crosstalk is critical for function and homeostasis. Although it is established that prion infection of neurons is necessary for clinical disease to occur, debate remains in the field as to the role played by glial cells, namely astrocytes and microglia, and whether these cells are beneficial to the host or further accelerate disease. Here, we review the current literature assessing the complex morphologies of astrocytes and microglia, and the crosstalk between these two cell types, in the prion-infected brain. Full article
(This article belongs to the Special Issue Pathogenesis of Prion Diseases)
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