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Open AccessArticle

Extracellular Prion Protein Aggregates in Nine Gerstmann–Sträussler–Scheinker Syndrome Subjects with Mutation P102L: A Micromorphological Study and Comparison with Literature Data

by Nikol Jankovska, Radoslav Matej and Tomas Olejar

Int. J. Mol. Sci. 2021, 22(24), 13303; https://doi.org/10.3390/ijms222413303 - 10 Dec 2021

Cited by 2 | Viewed by 2021

Abstract

Gerstmann–Sträussler–Scheinker syndrome (GSS) is a hereditary neurodegenerative disease characterized by extracellular aggregations of pathological prion protein (PrP) forming characteristic plaques. Our study aimed to evaluate the micromorphology and protein composition of these plaques in relation to age, disease duration, and co-expression of other [...] Read more.

Gerstmann–Sträussler–Scheinker syndrome (GSS) is a hereditary neurodegenerative disease characterized by extracellular aggregations of pathological prion protein (PrP) forming characteristic plaques. Our study aimed to evaluate the micromorphology and protein composition of these plaques in relation to age, disease duration, and co-expression of other pathogenic proteins related to other neurodegenerations. Hippocampal regions of nine clinically, neuropathologically, and genetically confirmed GSS subjects were investigated using immunohistochemistry and multichannel confocal fluorescent microscopy. Most pathognomic prion protein plaques were small (2–10 µm), condensed, globous, and did not contain any of the other investigated proteinaceous components, particularly dystrophic neurites. Equally rare (in two cases out of nine) were plaques over 50 µm having predominantly fibrillar structure and exhibit the presence of dystrophic neuritic structures; in one case, the plaques also included bulbous dystrophic neurites. Co-expression with hyperphosphorylated protein tau protein or amyloid beta-peptide (Aβ) in GSS PrP plaques is generally a rare observation, even in cases with comorbid neuropathology. The dominant picture of the GSS brain is small, condensed plaques, often multicentric, while presence of dystrophic neuritic changes accumulating hyperphosphorylated protein tau or Aβ in the PrP plaques are rare and, thus, their presence probably constitutes a trivial observation without any relationship to GSS development and progression. Full article

(This article belongs to the Special Issue Prions and Prion Diseases 2.0)

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10 pages, 2840 KiB

Open AccessArticle

Ethanolamine Is a New Anti-Prion Compound

by Keiji Uchiyama, Hideyuki Hara, Junji Chida, Agriani Dini Pasiana, Morikazu Imamura, Tsuyoshi Mori, Hanae Takatsuki, Ryuichiro Atarashi and Suehiro Sakaguchi

Int. J. Mol. Sci. 2021, 22(21), 11742; https://doi.org/10.3390/ijms222111742 - 29 Oct 2021

Cited by 5 | Viewed by 2197

Abstract

Prion diseases are a group of fatal neurodegenerative disorders caused by accumulation of proteinaceous infectious particles, or prions, which mainly consist of the abnormally folded, amyloidogenic prion protein, designated PrP^Sc. PrP^Sc is produced through conformational conversion of the cellular isoform [...] Read more.

Prion diseases are a group of fatal neurodegenerative disorders caused by accumulation of proteinaceous infectious particles, or prions, which mainly consist of the abnormally folded, amyloidogenic prion protein, designated PrP^Sc. PrP^Sc is produced through conformational conversion of the cellular isoform of prion protein, PrP^C, in the brain. To date, no effective therapies for prion diseases have been developed. In this study, we incidentally noticed that mouse neuroblastoma N2a cells persistently infected with 22L scrapie prions, termed N2aC24L1-3 cells, reduced PrP^Sc levels when cultured in advanced Dulbecco’s modified eagle medium (DMEM) but not in classic DMEM. PrP^C levels remained unchanged in prion-uninfected parent N2aC24 cells cultured in advanced DMEM. These results suggest that advanced DMEM may contain an anti-prion compound(s). We then successfully identified ethanolamine in advanced DMEM has an anti-prion activity. Ethanolamine reduced PrP^Sc levels in N2aC24L1-3 cells, but not PrP^C levels in N2aC24 cells. Also, oral administration of ethanolamine through drinking water delayed prion disease in mice intracerebrally inoculated with RML scrapie prions. These results suggest that ethanolamine could be a new anti-prion compound. Full article

(This article belongs to the Special Issue Prions and Prion Diseases 2.0)

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16 pages, 2713 KiB

Open AccessArticle

Prion Infectivity and PrP^BSE in the Peripheral and Central Nervous System of Cattle 8 Months Post Oral BSE Challenge

by Ivett Ackermann, Reiner Ulrich, Kerstin Tauscher, Olanrewaju I. Fatola, Markus Keller, James C. Shawulu, Mark Arnold, Stefanie Czub, Martin H. Groschup and Anne Balkema-Buschmann

Int. J. Mol. Sci. 2021, 22(21), 11310; https://doi.org/10.3390/ijms222111310 - 20 Oct 2021

Cited by 2 | Viewed by 2017

Abstract

After oral exposure of cattle with classical bovine spongiform encephalopathy (C-BSE), the infectious agent ascends from the gut to the central nervous system (CNS) primarily via the autonomic nervous system. However, the timeline of this progression has thus far remained widely undetermined. Previous [...] Read more.

After oral exposure of cattle with classical bovine spongiform encephalopathy (C-BSE), the infectious agent ascends from the gut to the central nervous system (CNS) primarily via the autonomic nervous system. However, the timeline of this progression has thus far remained widely undetermined. Previous studies were focused on later time points after oral exposure of animals that were already 4 to 6 months old when challenged. In contrast, in this present study, we have orally inoculated 4 to 6 weeks old unweaned calves with high doses of BSE to identify any possible BSE infectivity and/or PrP^BSE in peripheral nervous tissues during the first eight months post-inoculation (mpi). For the detection of BSE infectivity, we used a bovine PrP transgenic mouse bioassay, while PrP^BSE depositions were analyzed by immunohistochemistry (IHC) and by protein misfolding cyclic amplification (PMCA). We were able to show that as early as 8 mpi the thoracic spinal cord as well as the parasympathetic nodal ganglion of these animals contained PrP^BSE and BSE infectivity. This shows that the centripetal prion spread starts early after challenge at least in this age group, which represents an essential piece of information for the risk assessments for food, feed, and pharmaceutical products produced from young calves. Full article

(This article belongs to the Special Issue Prions and Prion Diseases 2.0)

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8 pages, 2043 KiB

Open AccessArticle

Circulation of Nor98 Atypical Scrapie in Portuguese Sheep Confirmed by Transmission of Isolates into Transgenic Ovine ARQ-PrP Mice

by Mafalda Casanova, Carla Machado, Paula Tavares, João Silva, Christine Fast, Anne Balkema-Buschmann, Martin H. Groschup and Leonor Orge

Int. J. Mol. Sci. 2021, 22(19), 10441; https://doi.org/10.3390/ijms221910441 - 28 Sep 2021

Cited by 1 | Viewed by 1607

Abstract

Portugal was among the first European countries to report cases of Atypical Scrapie (ASc), the dominant form of Transmissible Spongiform Encephalopathy (TSE) in Portuguese small ruminants. Although the diagnostic phenotypes observed in Portuguese ASc cases seem identical to those described for Nor98, unequivocal [...] Read more.

Portugal was among the first European countries to report cases of Atypical Scrapie (ASc), the dominant form of Transmissible Spongiform Encephalopathy (TSE) in Portuguese small ruminants. Although the diagnostic phenotypes observed in Portuguese ASc cases seem identical to those described for Nor98, unequivocal identification requires TSE strain-typing using murine bioassays. In this regard, we initiated characterization of ASc isolates from sheep either homozygous for the ARQ genotype or the classical scrapie-resistant ARR genotype. Isolates from such genotypes were transmitted to TgshpXI mice expressing ovine PrPARQ. Mean incubation periods were 414 ± 58 and 483 ± 107 days in mice inoculated with AL₁₄₁RQ/AF₁₄₁RQ and AL₁₄₁RR/AL₁₄₁RR sheep isolates, respectively. Both isolates produced lesion profiles similar to French ASc Nor98 ‘discordant cases’, where vacuolation was observed in the hippocampus (G6), cerebral cortex at the thalamus (G8) level, cerebellar white matter (W1) and cerebral peduncles (W3). Immunohistochemical PrP^Sc deposition was observed in the hippocampus, cerebellar cortex, cerebellar white matter and cerebral peduncles in the form of aggregates and fine granules. These findings were consistent with previously reported cases of ASc Nor98 transmitted to transgenic TgshpXI mice, confirming that the ASc strain present in Portuguese sheep corresponds to ASc Nor98. Full article

(This article belongs to the Special Issue Prions and Prion Diseases 2.0)

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12 pages, 1941 KiB

Open AccessArticle

Vaporized Hydrogen Peroxide and Ozone Gas Synergistically Reduce Prion Infectivity on Stainless Steel Wire

by Hideyuki Hara, Junji Chida, Agriani Dini Pasiana, Keiji Uchiyama, Yutaka Kikuchi, Tomoko Naito, Yuichi Takahashi, Junji Yamamura, Hisashi Kuromatsu and Suehiro Sakaguchi

Int. J. Mol. Sci. 2021, 22(6), 3268; https://doi.org/10.3390/ijms22063268 - 23 Mar 2021

Cited by 2 | Viewed by 2404

Abstract

Prions are infectious agents causing prion diseases, which include Creutzfeldt–Jakob disease (CJD) in humans. Several cases have been reported to be transmitted through medical instruments that were used for preclinical CJD patients, raising public health concerns on iatrogenic transmissions of the disease. Since [...] Read more.

Prions are infectious agents causing prion diseases, which include Creutzfeldt–Jakob disease (CJD) in humans. Several cases have been reported to be transmitted through medical instruments that were used for preclinical CJD patients, raising public health concerns on iatrogenic transmissions of the disease. Since preclinical CJD patients are currently difficult to identify, medical instruments need to be adequately sterilized so as not to transmit the disease. In this study, we investigated the sterilizing activity of two oxidizing agents, ozone gas and vaporized hydrogen peroxide, against prions fixed on stainless steel wires using a mouse bioassay. Mice intracerebrally implanted with prion-contaminated stainless steel wires treated with ozone gas or vaporized hydrogen peroxide developed prion disease later than those implanted with control prion-contaminated stainless steel wires, indicating that ozone gas and vaporized hydrogen peroxide could reduce prion infectivity on wires. Incubation times were further elongated in mice implanted with prion-contaminated stainless steel wires treated with ozone gas-mixed vaporized hydrogen peroxide, indicating that ozone gas mixed with vaporized hydrogen peroxide reduces prions on these wires more potently than ozone gas or vaporized hydrogen peroxide. These results suggest that ozone gas mixed with vaporized hydrogen peroxide might be more useful for prion sterilization than ozone gas or vaporized hydrogen peroxide alone. Full article

(This article belongs to the Special Issue Prions and Prion Diseases 2.0)

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Review

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12 pages, 565 KiB

Open AccessReview

Virus Infection, Genetic Mutations, and Prion Infection in Prion Protein Conversion

by Hideyuki Hara and Suehiro Sakaguchi

Int. J. Mol. Sci. 2021, 22(22), 12439; https://doi.org/10.3390/ijms222212439 - 18 Nov 2021

Cited by 3 | Viewed by 2967

Abstract

Conformational conversion of the cellular isoform of prion protein, PrP^C, into the abnormally folded, amyloidogenic isoform, PrP^Sc, is an underlying pathogenic mechanism in prion diseases. The diseases manifest as sporadic, hereditary, and acquired disorders. Etiological mechanisms driving the conversion [...] Read more.

Conformational conversion of the cellular isoform of prion protein, PrP^C, into the abnormally folded, amyloidogenic isoform, PrP^Sc, is an underlying pathogenic mechanism in prion diseases. The diseases manifest as sporadic, hereditary, and acquired disorders. Etiological mechanisms driving the conversion of PrP^C into PrP^Sc are unknown in sporadic prion diseases, while prion infection and specific mutations in the PrP gene are known to cause the conversion of PrP^C into PrP^Sc in acquired and hereditary prion diseases, respectively. We recently reported that a neurotropic strain of influenza A virus (IAV) induced the conversion of PrP^C into PrP^Sc as well as formation of infectious prions in mouse neuroblastoma cells after infection, suggesting the causative role of the neuronal infection of IAV in sporadic prion diseases. Here, we discuss the conversion mechanism of PrP^C into PrP^Sc in different types of prion diseases, by presenting our findings of the IAV infection-induced conversion of PrP^C into PrP^Sc and by reviewing the so far reported transgenic animal models of hereditary prion diseases and the reverse genetic studies, which have revealed the structure-function relationship for PrP^C to convert into PrP^Sc after prion infection. Full article

(This article belongs to the Special Issue Prions and Prion Diseases 2.0)

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13 pages, 352 KiB

Open AccessReview

microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD)

by Aileen I. Pogue and Walter J. Lukiw

Int. J. Mol. Sci. 2021, 22(17), 9198; https://doi.org/10.3390/ijms22179198 - 25 Aug 2021

Cited by 17 | Viewed by 3751

Abstract

The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated [...] Read more.

The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer’s disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host’s adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible. Full article

(This article belongs to the Special Issue Prions and Prion Diseases 2.0)

21 pages, 7343 KiB

Open AccessReview

How an Infection of Sheep Revealed Prion Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders

by George A. Carlson and Stanley B. Prusiner

Int. J. Mol. Sci. 2021, 22(9), 4861; https://doi.org/10.3390/ijms22094861 - 4 May 2021

Cited by 25 | Viewed by 5773

Abstract

Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted [...] Read more.

Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted perspective arose from the prion hypothesis, which resulted from investigations on scrapie, a common transmissible disease of sheep and goats. The prion hypothesis argued that the causative infectious agent of scrapie was a novel proteinaceous pathogen devoid of functional nucleic acids and distinct from viruses, viroids, and bacteria. At the time, it seemed impossible that an infectious agent like the one causing scrapie could replicate and exist as diverse microbiological strains without nucleic acids. However, aggregates of a misfolded host-encoded protein, designated the prion protein (PrP), were shown to be the cause of scrapie as well as Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS), which are similar NDs in humans. This review discusses historical research on diseases caused by PrP misfolding, emphasizing principles of pathogenesis that were later found to be core features of other NDs. For example, the discovery that familial prion diseases can be caused by mutations in PrP was important for understanding prion replication and disease susceptibility not only for rare PrP diseases but also for far more common NDs involving other proteins. We compare diseases caused by misfolding and aggregation of APP-derived Aβ peptides, tau, and α-synuclein with PrP prion disorders and argue for the classification of NDs caused by misfolding of these proteins as prion diseases. Deciphering the molecular pathogenesis of NDs as prion-mediated has provided new approaches for finding therapies for these intractable, invariably fatal disorders and has revolutionized the field. Full article

(This article belongs to the Special Issue Prions and Prion Diseases 2.0)

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