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Biomolecules
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Prions and Prion-Like Mechanisms in Disease and Biological Function
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Prions and Prion-Like Mechanisms in Disease and Biological Function

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 42086

Special Issue Editors

Prof. Dr. Parmjit S. Jat

E-Mail Website
Guest Editor
MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London W1W 7FF, UK
Interests: prion biology; prion propagation; prion induced toxicity; cell models; cancer biology; regeneration; cell immortalisation
Dr. Jan Bieschke

E-Mail Website
Guest Editor
MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London W1W 7FF, UK
Interests: protein structure and folding; self-assembly mechanisms; chaperone-like molecules
Dr. Wei-Feng Xue

E-Mail Website
Guest Editor
Kent Fungal Group, School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK
Interests: amyloid; prions; protein folding; protein interactions; biophysics

Special Issue Information

Dear Colleagues,

Research into prions has vastly expanded our knowledge and understanding of an infectious pathogen. Prions are replication-competent assemblies of a host-encoded protein, which lack nucleic acid for encoding pathogenic information. Rather, their properties are encoded in the conformation of the peptide chains, giving rise to “strains” with different pathogenic phenotypes and species barriers based on the structural properties of the assembly and subtle differences in the sequence of the precursor proteins. They are involved in devastating neurodegenerative diseases, such as Creutzfeldt–Jakob disease, kuru and scrapie, but the concept of prions, and prion-like assemblies and their replication mechanisms has expanded, and analogous protein-based functional inheritance mechanisms exist in yeast and fungi.

Similar replication mechanisms have been identified in diseases such as Alzheimer’s and Parkinson’s disease, in which amyloid aggregates can act as “prion-like infectious entities” on the molecular level. These amyloid aggregates are able to cross cellular membranes, thereby propagating disease. However, despite sharing the same cross-beta core structure, some prions and prion-like amyloid assemblies are disease-associated and transmissible, while others are inert and tolerated. Recent data suggest that prion transmission can be dissociated from toxicity, raising the question of why some prion and prion-like amyloid aggregates are toxic while others are not, and how self-replication, infectivity, and toxicity are linked at the structural and mechanistic level. These key questions of fundamental importance will be highlighted in this Special Issue. They are by their nature multidisciplinary, and we thus strongly welcome approaches that merge structural, cellular, and molecular biology, biochemistry, biophysics, imaging and computational techniques on topics including, but not limited to the following:

Structural properties of prions and amyloid

Prion-like mechanisms in neurodegenerative disease, in systemic diseases, and in biological functions

Structure–toxicity and structure–infectivity relationships

Structural and dynamic basis of prion strains

Functional role of disease-associated mutations

Prof. Dr. Parmjit S. Jat
Dr. Jan Bieschke
Dr. Wei-Feng Xue
Guest Editors

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. Biomolecules 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 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

  • prion
  • amyloid
  • polymorphism
  • fibril structure
  • assembly dynamics
  • toxic and infective potential

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Published Papers (8 papers)

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Research

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13 pages, 1947 KiB  
Article
The Effects of Fibrinogen’s Interactions with Its Neuronal Receptors, Intercellular Adhesion Molecule-1 and Cellular Prion Protein
by Nurul Sulimai, Jason Brown and David Lominadze
Biomolecules 2021, 11(9), 1381; https://doi.org/10.3390/biom11091381 - 18 Sep 2021
Cited by 8 | Viewed by 7167
Abstract
Neuroinflammatory diseases, such as Alzheimer’s disease (AD) and traumatic brain injury (TBI), are associated with the extravascular deposition of the fibrinogen (Fg) derivative fibrin and are accompanied with memory impairment. We found that during the hyperfibrinogenemia that typically occurs during AD and TBI, [...] Read more.
Neuroinflammatory diseases, such as Alzheimer’s disease (AD) and traumatic brain injury (TBI), are associated with the extravascular deposition of the fibrinogen (Fg) derivative fibrin and are accompanied with memory impairment. We found that during the hyperfibrinogenemia that typically occurs during AD and TBI, extravasated Fg was associated with amyloid beta and astrocytic cellular prion protein (PrPC). These effects coincided with short-term memory (STM) reduction and neurodegeneration. However, the mechanisms of a direct Fg–neuron interaction and its functional role in neurodegeneration are still unclear. Cultured mouse brain neurons were treated with Fg in the presence or absence of function-blockers of its receptors, PrPC or intercellular adhesion molecule-1 (ICAM-1). Associations of Fg with neuronal PrPC and ICAM-1 were characterized. The expression of proinflammatory marker interleukin 6 (IL-6) and the generation of reactive oxygen species (ROS), mitochondrial superoxide, and nitrite in neurons were assessed. Fg-induced neuronal death was also evaluated. A strong association of Fg with neuronal PrPC and ICAM-1, accompanied with overexpression of IL-6 and enhanced generation of ROS, mitochondrial superoxide, and nitrite as well as the resulting neuronal death, was found. These effects were reduced by blocking the function of neuronal PrPC and ICAM-1, suggesting that the direct interaction of Fg with its neuronal receptors can induce overexpression of IL-6 and increase the generation of ROS, nitrite, and mitochondrial superoxide, ultimately leading to neuronal death. These effects can be a mechanism of neurodegeneration and the resultant memory reduction seen during TBI and AD. Full article
(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)
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12 pages, 4471 KiB  
Article
Involvement of Cellular Prion Protein in Invasion and Metastasis of Lung Cancer by Inducing Treg Cell Development
by Seunghwa Cha, Mi-Ji Sin, Mo-Jong Kim, Hee-Jun Kim, Yong-Sun Kim, Eun-Kyoung Choi and Mi-Yeon Kim
Biomolecules 2021, 11(2), 285; https://doi.org/10.3390/biom11020285 - 15 Feb 2021
Cited by 10 | Viewed by 2847
Abstract
The cellular prion protein (PrPC) is a cell surface glycoprotein expressed in many cell types that plays an important role in normal cellular processes. However, an increase in PrPC expression has been associated with a variety of human cancers, where [...] Read more.
The cellular prion protein (PrPC) is a cell surface glycoprotein expressed in many cell types that plays an important role in normal cellular processes. However, an increase in PrPC expression has been associated with a variety of human cancers, where it may be involved in resistance to the proliferation and metastasis of cancer cells. PrP-deficient (Prnp0/0) and PrP-overexpressing (Tga20) mice were studied to evaluate the role of PrPC in the invasion and metastasis of cancer. Tga20 mice, with increased PrPC, died more quickly from lung cancer than did the Prnp0/0 mice, and this effect was associated with increased transforming growth factor-beta (TGF-β) and programmed death ligand-1 (PD-L1), which are important for the development and function of regulatory T (Treg) cells. The number of FoxP3+CD25+ Treg cells was increased in Tga20 mice compared to Prnp0/0 mice, but there was no significant difference in either natural killer or cytotoxic T cell numbers. In addition, mice infected with the ME7 scrapie strain had decreased numbers of Treg cells and decreased expression of TGF-β and PD-L1. These results suggest that PrPC plays an important role in invasion and metastasis of cancer cells by inducing Treg cells through upregulation of TGF-β and PD-L1 expression. Full article
(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)
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Review

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15 pages, 1544 KiB  
Review
Essential Components of Synthetic Infectious Prion Formation De Novo
by Kezia Jack, Graham S. Jackson and Jan Bieschke
Biomolecules 2022, 12(11), 1694; https://doi.org/10.3390/biom12111694 - 16 Nov 2022
Cited by 4 | Viewed by 2897
Abstract
Prion diseases are a class of neurodegenerative diseases that are uniquely infectious. Whilst their general replication mechanism is well understood, the components required for the formation and propagation of highly infectious prions are poorly characterized. The protein-only hypothesis posits that the prion protein [...] Read more.
Prion diseases are a class of neurodegenerative diseases that are uniquely infectious. Whilst their general replication mechanism is well understood, the components required for the formation and propagation of highly infectious prions are poorly characterized. The protein-only hypothesis posits that the prion protein (PrP) is the only component of the prion; however, additional co-factors are required for its assembly into infectious prions. These can be provided by brain homogenate, but synthetic lipids and non-coding RNA have also been used in vitro. Here, we review a range of experimental approaches, which generate PrP amyloid assemblies de novo. These synthetic PrP assemblies share some, but not necessarily all, properties of genuine infectious prions. We will discuss the different experimental approaches, how a prion is defined, the non-protein requirements of a prion, and provide an overview of the current state of prion amplification and generation in vitro. Full article
(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)
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16 pages, 1275 KiB  
Review
RT-QuIC and Related Assays for Detecting and Quantifying Prion-like Pathological Seeds of α-Synuclein
by Ankit Srivastava, Parvez Alam and Byron Caughey
Biomolecules 2022, 12(4), 576; https://doi.org/10.3390/biom12040576 - 14 Apr 2022
Cited by 19 | Viewed by 6645
Abstract
Various disease-associated forms or strains of α-synuclein (αSynD) can spread and accumulate in a prion-like fashion during synucleinopathies such as Parkinson’s disease (PD), Lewy body dementia (DLB), and multiple system atrophy (MSA). This capacity for self-propagation has enabled the development of [...] Read more.
Various disease-associated forms or strains of α-synuclein (αSynD) can spread and accumulate in a prion-like fashion during synucleinopathies such as Parkinson’s disease (PD), Lewy body dementia (DLB), and multiple system atrophy (MSA). This capacity for self-propagation has enabled the development of seed amplification assays (SAAs) that can detect αSynD in clinical samples. Notably, α-synuclein real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) assays have evolved as ultrasensitive, specific, and relatively practical methods for detecting αSynD in a variety of biospecimens including brain tissue, CSF, skin, and olfactory mucosa from synucleinopathy patients. However, αSyn SAAs still lack concordance in detecting MSA and familial forms of PD/DLB, and the assay parameters show poor correlations with various clinical measures. End-point dilution analysis in αSyn RT-QuIC assays allows for the quantitation of relative amounts of αSynD seeding activity that may correlate moderately with clinical measures and levels of other biomarkers. Herein, we review recent advancements in α-synuclein SAAs for detecting αSynD and describe in detail the modified Spearman–Karber quantification algorithm used with end-point dilutions. Full article
(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)
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11 pages, 1172 KiB  
Review
Biological Functions of the Intrinsically Disordered N-Terminal Domain of the Prion Protein: A Possible Role of Liquid–Liquid Phase Separation
by Stella A. Polido, Janine Kamps and Jörg Tatzelt
Biomolecules 2021, 11(8), 1201; https://doi.org/10.3390/biom11081201 - 12 Aug 2021
Cited by 2 | Viewed by 3121
Abstract
The mammalian prion protein (PrPC) is composed of a large intrinsically disordered N-terminal and a structured C-terminal domain, containing three alpha-helical regions and a short, two-stranded beta-sheet. Traditionally, the activity of a protein was linked to the ability of the polypeptide [...] Read more.
The mammalian prion protein (PrPC) is composed of a large intrinsically disordered N-terminal and a structured C-terminal domain, containing three alpha-helical regions and a short, two-stranded beta-sheet. Traditionally, the activity of a protein was linked to the ability of the polypeptide chain to adopt a stable secondary/tertiary structure. This concept has been extended when it became evident that intrinsically disordered domains (IDDs) can participate in a broad range of defined physiological activities and play a major functional role in several protein classes including transcription factors, scaffold proteins, and signaling molecules. This ability of IDDs to engage in a variety of supramolecular complexes may explain the large number of PrPC-interacting proteins described. Here, we summarize diverse physiological and pathophysiological activities that have been described for the unstructured N-terminal domain of PrPC. In particular, we focus on subdomains that have been conserved in evolution. Full article
(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)
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18 pages, 594 KiB  
Review
Prion-Like Proteins in Phase Separation and Their Link to Disease
by Macy L. Sprunger and Meredith E. Jackrel
Biomolecules 2021, 11(7), 1014; https://doi.org/10.3390/biom11071014 - 11 Jul 2021
Cited by 25 | Viewed by 9816
Abstract
Aberrant protein folding underpins many neurodegenerative diseases as well as certain myopathies and cancers. Protein misfolding can be driven by the presence of distinctive prion and prion-like regions within certain proteins. These prion and prion-like regions have also been found to drive liquid-liquid [...] Read more.
Aberrant protein folding underpins many neurodegenerative diseases as well as certain myopathies and cancers. Protein misfolding can be driven by the presence of distinctive prion and prion-like regions within certain proteins. These prion and prion-like regions have also been found to drive liquid-liquid phase separation. Liquid-liquid phase separation is thought to be an important physiological process, but one that is prone to malfunction. Thus, aberrant liquid-to-solid phase transitions may drive protein aggregation and fibrillization, which could give rise to pathological inclusions. Here, we review prions and prion-like proteins, their roles in phase separation and disease, as well as potential therapeutic approaches to counter aberrant phase transitions. Full article
(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)
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21 pages, 1482 KiB  
Review
Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases
by Sungtae Yoon, Gyeongyun Go, Yeomin Yoon, Jiho Lim, Gaeun Lee and Sanghun Lee
Biomolecules 2021, 11(6), 784; https://doi.org/10.3390/biom11060784 - 22 May 2021
Cited by 6 | Viewed by 5053
Abstract
A cellular prion protein (PrPC) is a ubiquitous cell surface glycoprotein, and its physiological functions have been receiving increased attention. Endogenous PrPC is present in various kidney tissues and undergoes glomerular filtration. In prion diseases, abnormal prion proteins are found [...] Read more.
A cellular prion protein (PrPC) is a ubiquitous cell surface glycoprotein, and its physiological functions have been receiving increased attention. Endogenous PrPC is present in various kidney tissues and undergoes glomerular filtration. In prion diseases, abnormal prion proteins are found to accumulate in renal tissues and filtered into urine. Urinary prion protein could serve as a diagnostic biomarker. PrPC plays a role in cellular signaling pathways, reno-protective effects, and kidney iron uptake. PrPC signaling affects mitochondrial function via the ERK pathway and is affected by the regulatory influence of microRNAs, small molecules, and signaling proteins. Targeting PrPC in acute and chronic kidney disease could help improve iron homeostasis, ameliorate damage from ischemia/reperfusion injury, and enhance the efficacy of mesenchymal stem/stromal cell or extracellular vesicle-based therapeutic strategies. PrPC may also be under the influence of BMP/Smad signaling and affect the progression of TGF-β-related renal fibrosis. PrPC conveys TNF-α resistance in some renal cancers, and therefore, the coadministration of anti-PrPC antibodies improves chemotherapy. PrPC can be used to design antibody–drug conjugates, aptamer–drug conjugates, and customized tissue inhibitors of metalloproteinases to suppress cancer. With preclinical studies demonstrating promising results, further research on PrPC in the kidney may lead to innovative PrPC-based therapeutic strategies for renal disease. Full article
(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)
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Other

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6 pages, 227 KiB  
Commentary
Recent Advances in Our Molecular and Mechanistic Understanding of Misfolded Cellular Proteins in Alzheimer’s Disease (AD) and Prion Disease (PrD)
by Walter J. Lukiw
Biomolecules 2022, 12(2), 166; https://doi.org/10.3390/biom12020166 - 20 Jan 2022
Cited by 15 | Viewed by 2916
Abstract
Naturally occurring neuron-abundant proteins including amyloid Aβ42 peptide and the microtubule-associated protein tau (MAPT) can, over time and under pathological situations, assume atypical conformations, altering their normal biological structure and function, and causing them to aggregate into insoluble and neurotoxic intracellular inclusions. These [...] Read more.
Naturally occurring neuron-abundant proteins including amyloid Aβ42 peptide and the microtubule-associated protein tau (MAPT) can, over time and under pathological situations, assume atypical conformations, altering their normal biological structure and function, and causing them to aggregate into insoluble and neurotoxic intracellular inclusions. These misfolded proteins ultimately contribute to the pathogenesis of several progressive, age-related and ultimately lethal human neurodegenerative disorders. The molecular mechanism of this pathological phenomenon of neuronal protein misfolding lends support to the ‘prion hypothesis’, which predicts that the aberrant folding of endogenous natural protein structures into unusual pathogenic isoforms can induce the atypical folding of other similar brain-abundant proteins, underscoring the age-related, progressive nature and potential transmissible and spreading capabilities of the aberrant protein isoforms that drive these invariably fatal neurological syndromes. The abnormal folding and aggregation of host proteins is a consistent feature of both amyloidopathies and tauopathies that encompass a continuous spectrum of brain diseases that include Alzheimer’s disease (AD), prion disorders (PrD) such as scrapie in sheep and goats (Bovidae), experimental prion infection of rodents (Muridae), Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS) in humans (Hominidae), and other fatal prion-driven neurological disorders. Because AD patients accumulate both misfolded tau and Aβ peptides, AD may be somewhat unique as the first example of a ‘double prion disorder’. This commentary will examine current research trends in this fascinating research area, with a special emphasis on AD and PrD, and the novel pathological misfolded protein processes common to both intractable neurological disorders. Full article
(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)
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