scholarly journals Region-specific glial homeostatic signature in prion diseases is replaced by a uniform neuroinflammation signature, common for brain regions and prion strains with different cell tropism

2020 ◽  
Vol 137 ◽  
pp. 104783 ◽  
Author(s):  
Natallia Makarava ◽  
Jennifer Chen-Yu Chang ◽  
Kara Molesworth ◽  
Ilia V. Baskakov
Keyword(s):  
Prion Diseases ◽  
Brain Regions ◽  
Cell Tropism ◽  
Prion Strains

scholarly journals Loss of region-specific glial homeostatic signature in prion diseases

2019 ◽  
Author(s):  
Natallia Makarava ◽  
Jennifer Chen-Yu Chang ◽  
Kara Molesworth ◽  
Ilia V. Baskakov
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Diseases ◽  
Prion Diseases ◽  
Clinical Signs ◽  
Gene Expression Signature ◽  
Brain Regions ◽  
Prion Infection ◽  
Prion Strains ◽  
Advanced Stages ◽  
Disease Region

AbstractBackgroundChronic neuroinflammation is recognized as a major neuropathological hallmark in a broad spectrum of neurodegenerative diseases including Alzheimer’s, Parkinson’s, Frontal Temporal Dementia, Amyotrophic Lateral Sclerosis, and prion diseases. Both microglia and astrocytes exhibit region-specific homeostatic transcriptional identities, which under chronic neurodegeneration, transform into reactive phenotypes in a region- and disease-specific manner. Little is known about region-specific identity of glia in prion diseases. The current study was designed to determine whether the region-specific homeostatic signature of glia changes with the progression of prion diseases, and whether these changes occur in a region-dependent or universal manner. Also of interest was whether different prion strains give rise to different reactive phenotypes.MethodsTo answer these questions, we analyzed gene expression in thalamus, cortex, hypothalamus and hippocampus of mice infected with 22L and ME7 prion strains using Nanostring Neuroinflammation panel at subclinical, early clinical and advanced stages of the disease.ResultsWe found that at the preclinical stage of the disease, region-specific homeostatic identities were preserved. However, with the appearance of clinical signs, region-specific signatures were partially lost and replaced with a neuroinflammation signature. While the same sets of genes were activated by both prion strains, the timing of neuroinflammation and the degree of activation in different brain regions was strain-specific. Changes in astrocyte function scored at the top of activated pathways. Moreover, clustering analysis suggested that the astrocyte function pathway responded to prion infection prior to activated microglia or neuron and neurotransmission pathways.ConclusionsThe current work established neuroinflammation gene expression signature associated with prion diseases. Our results illustrate that with the disease progression, the region-specific homeostatic transcriptome signatures are replaced by region-independent neuroinflammation signature, which was common for prion strains with different cell tropism. The prion-associated neuroinflammation signature identified in the current study overlapped only partially with the microglia degenerative phenotype and the disease-associated microglia phenotype reported for animal models of other neurodegenerative diseases.

scholarly journals Loss of region-specific glial homeostatic signature in prion diseases

2019 ◽  
Author(s):  
Natallia Makarava ◽  
Jennifer Chen-Yu Chang ◽  
Kara Molesworth ◽  
Ilia V Baskakov
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Diseases ◽  
Prion Diseases ◽  
Clinical Signs ◽  
Gene Expression Signature ◽  
Brain Regions ◽  
Prion Infection ◽  
Prion Strains ◽  
Advanced Stages ◽  
Disease Region

Abstract Background Chronic neuroinflammation is recognized as a major neuropathological hallmark in a broad spectrum of neurodegenerative diseases including Alzheimer’s, Parkinson’s, Frontal Temporal Dementia, Amyotrophic Lateral Sclerosis, and prion diseases. Both microglia and astrocytes exhibit region-specific homeostatic transcriptional identities, which under chronic neurodegeneration, transform into reactive phenotypes in a region- and disease-specific manner. Little is known about region-specific identity of glia in prion diseases. The current study was designed to determine whether the region-specific homeostatic signature of glia changes with the progression of prion diseases, and whether these changes occur in a region-dependent or universal manner. Also of interest was whether different prion strains give rise to different reactive phenotypes. Methods To answer these questions, we analyzed gene expression in thalamus, cortex, hypothalamus and hippocampus of mice infected with 22L and ME7 prion strains using Nanostring Neuroinflammation panel at subclinical, early clinical and advanced stages of the disease. Results We found that at the preclinical stage of the disease, region-specific homeostatic identities were preserved. However, with the appearance of clinical signs, region-specific signatures were partially lost and replaced with a neuroinflammation signature. While the same sets of genes were activated by both prion strains, the timing of neuroinflammation and the degree of activation in different brain regions was strain-specific. Changes in astrocyte function scored at the top of activated pathways. Moreover, clustering analysis suggested that the astrocyte function pathway responded to prion infection prior to activated microglia or neuron and neurotransmission pathways. Conclusions The current work established neuroinflammation gene expression signature associated with prion diseases. Our results illustrate that with the disease progression, the region-specific homeostatic transcriptome signatures are replaced by region-independent neuroinflammation signature, which was common for prion strains with different cell tropism. The prion-associated neuroinflammation signature identified in the current study overlapped only partially with the microglia degenerative phenotype and the disease-associated microglia phenotype reported for animal models of other neurodegenerative diseases.

scholarly journals Differential Accumulation of Misfolded Prion Strains in Natural Hosts of Prion Diseases

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2453
Author(s):  
Zoe J. Lambert ◽  
Justin J. Greenlee ◽  
Eric D. Cassmann ◽  
M. Heather West Greenlee
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Brain Regions ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Prion Strains ◽  
Natural Hosts ◽  
Different Strains

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of neurodegenerative protein misfolding diseases that invariably cause death. TSEs occur when the endogenous cellular prion protein (PrPC) misfolds to form the pathological prion protein (PrPSc), which templates further conversion of PrPC to PrPSc, accumulates, and initiates a cascade of pathologic processes in cells and tissues. Different strains of prion disease within a species are thought to arise from the differential misfolding of the prion protein and have different clinical phenotypes. Different strains of prion disease may also result in differential accumulation of PrPSc in brain regions and tissues of natural hosts. Here, we review differential accumulation that occurs in the retinal ganglion cells, cerebellar cortex and white matter, and plexuses of the enteric nervous system in cattle with bovine spongiform encephalopathy, sheep and goats with scrapie, cervids with chronic wasting disease, and humans with prion diseases. By characterizing TSEs in their natural host, we can better understand the pathogenesis of different prion strains. This information is valuable in the pursuit of evaluating and discovering potential biomarkers and therapeutics for prion diseases.

scholarly journals Cholesterol transporter ATP-binding cassette A1 (ABCA1) is elevated in prion disease and affects PrPC and PrPSc concentrations in cultured cells

2008 ◽  
Vol 89 (6) ◽  
pp. 1525-1532 ◽  
Author(s):  
Rajeev Kumar ◽  
Denise McClain ◽  
Rebecca Young ◽  
George A. Carlson
Keyword(s):  
Prion Disease ◽  
Cultured Cells ◽  
Prion Diseases ◽  
Neuroblastoma Cells ◽  
Direct Consequence ◽  
Brain Regions ◽  
Atp Binding ◽  
N2a Cells ◽  
Atp Binding Cassette

Prion diseases are transmissible neurodegenerative disorders of prion protein (PrP) conformation. Prion replication by conversion of benign PrPC isoforms into disease-specific PrPSc isoforms is intimately involved in prion disease pathogenesis and may be initiated in cholesterol-rich caveolae-like domains (CLD). Concentrations of the cholesterol transporter ATP-binding cassette A1 protein (ABCA1) are elevated in pre-clinical scrapie prion-infected mice and in prion-infected cells in vitro. Elevation of ABCA1 in prion-infected brain is not a direct consequence of local PrPSc accumulation, indeed levels of ABCA1 are comparable in brain regions that differ dramatically in the amount of PrPSc. Similarly, ABCA1 concentrations are identical in normal mice, transgenic mice overexpressing PrP and PrP knockout mice. In contrast, PrPC and PrPSc levels, but not Prnp mRNA, were increased by overexpression of ABCA1 in N2a neuroblastoma cells and scrapie prion-infected N2a cells (ScN2a). Conversely, RNAi-mediated knock down of Abca1 expression decreased the concentrations of PrPC in N2a cells and of PrPSc in ScN2a cells. These results suggest that ABCA1's effects on PrPC levels are post-translational and may reflect an increase in of PrPC stability, mediated either indirectly by increasing membrane cholesterol and CLD formation or by other functions of ABCA1. The increased supply of PrPC available for conversion would lead to increased PrPSc formation.

scholarly journals Neuroinvasion in Prion Diseases: The Roles of Ascending Neural Infection and Blood Dissemination

2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Sílvia Sisó ◽  
Lorenzo González ◽  
Martin Jeffrey
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Prion Protein ◽  
Prion Diseases ◽  
Autonomic Nerves ◽  
Peripheral Organs ◽  
Prion Strains ◽  
New Variant ◽  
Jakob Disease ◽  
The Central Nervous System

Prion disorders are infectious, neurodegenerative diseases that affect humans and animals. Susceptibility to some prion diseases such as kuru or the new variant of Creutzfeldt-Jakob disease in humans and scrapie in sheep and goats is influenced by polymorphisms of the coding region of the prion protein gene, while other prion disorders such as fatal familial insomnia, familial Creutzfeldt-Jakob disease, or Gerstmann-Straussler-Scheinker disease in humans have an underlying inherited genetic basis. Several prion strains have been demonstrated experimentally in rodents and sheep. The progression and pathogenesis of disease is influenced by both genetic differences in the prion protein and prion strain. Some prion diseases only affect the central nervous system whereas others involve the peripheral organs prior to neuroinvasion. Many experiments undertaken in different species and using different prion strains have postulated common pathways of neuroinvasion. It is suggested that prions access the autonomic nerves innervating peripheral organs and tissues to finally reach the central nervous system. We review here published data supporting this view and additional data suggesting that neuroinvasion may concurrently or independently involve the blood vascular system.

Comparison of Brain PrPd Distribution in Ovine BSE and Scrapie

2011 ◽  
Vol 48 (6) ◽  
pp. 1101-1108 ◽  
Author(s):  
S. Lezmi ◽  
T. Seuberlich ◽  
A. Oevermann ◽  
T. Baron ◽  
A. Bencsik
Keyword(s):  
Frontal Cortex ◽  
Prion Diseases ◽  
Piriform Cortex ◽  
Small Ruminants ◽  
Infected Sheep ◽  
Spongiform Encephalopathy ◽  
Genotype Distribution ◽  
Prion Strains ◽  
Incubation Periods ◽  
The Brain

Scrapie and bovine spongiform encephalopathy (BSE) are both prion diseases affecting ruminants, and these diseases do not share the same public health concerns. Surveillance of the BSE agent in small ruminants has been a great challenge, and the recent identification of diverse prion diseases in ruminants has led to the development of new methods for strain typing. In our study, using immunohistochemistry (IHC), we assessed the distribution of PrPd in the brains of 2 experimentally BSE-infected sheep with the ARQ/ARQ genotype. Distribution of PrPd in the brain, from the spinal cord to the frontal cortex, was remarkably similar in the 2 sheep despite different inoculation routes and incubation periods. Comparatively, overall PrPd brain distribution, evaluated by IHC, in 19 scrapie cases with the ARQ/ARQ, ARQ/VRQ, and VRQ/VRQ genotypes, in some cases showed similarities to the experimentally BSE-infected sheep. There was no exclusive neuroanatomical site with a characteristic and specific PrPd type of accumulation induced by the BSE agent. However, a detailed analysis of the topography, types, and intensity of PrPd deposits in the frontal cortex, striatum, piriform cortex, hippocampus, mesencephalon, and cerebellum allowed the BSE-affected sheep group to be distinguished from the 19 scrapie cases analyzed in our study. These results strengthen and emphasize the potential interest of PrPd brain mapping to help in identifying prion strains in small ruminants.

scholarly journals Small Molecules with Anti-Prion Activity

2020 ◽  
Vol 27 (33) ◽  
pp. 5446-5479 ◽  
Author(s):  
Carlo Mustazza ◽  
Marco Sbriccoli ◽  
Paola Minosi ◽  
Carla Raggi
Keyword(s):  
High Throughput Screening ◽  
Prion Diseases ◽  
Membrane Domains ◽  
Native Conformation ◽  
Cellular Targets ◽  
Prion Strains ◽  
Structure Activity ◽  
Mediated Oxidation ◽  
Indirect Action

Prion pathologies are fatal neurodegenerative diseases caused by the misfolding of the physiological Prion Protein (PrP<sup>C</sup>) into a &#946;-structure-rich isoform called PrP<sup>Sc</sup>. To date, there is no available cure for prion diseases and just a few clinical trials have been carried out. The initial approach in the search of anti-prion agents had PrP<sup>Sc</sup> as a target, but the existence of different prion strains arising from alternative conformations of PrP<sup>Sc</sup>, limited the efficacy of the ligands to a straindependent ability. That has shifted research to PrP<sup>C</sup> ligands, which either act as chaperones, by stabilizing the native conformation, or inhibit its interaction with PrP<sup>Sc</sup>. The role of transition-metal mediated oxidation processes in prion misfolding has also been investigated. Another promising approach is the indirect action via other cellular targets, like membrane domains or the Protein- Folding Activity of Ribosomes (PFAR). Also, new prion-specific high throughput screening techniques have been developed. However, so far no substance has been found to be able to extend satisfactorily survival time in animal models of prion diseases. This review describes the main features of the Structure-Activity Relationship (SAR) of the various chemical classes of anti-prion agents.

scholarly journals PrP glycoforms are associated in a strain-specific ratio in native PrPSc

2005 ◽  
Vol 86 (9) ◽  
pp. 2635-2644 ◽  
Author(s):  
Azadeh Khalili-Shirazi ◽  
Linda Summers ◽  
Jacqueline Linehan ◽  
Gary Mallinson ◽  
David Anstee ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Normal Brain ◽  
Western Blots ◽  
Prion Strains ◽  
Specific Manner ◽  
First Time

Prion diseases involve conversion of host-encoded cellular prion protein (PrPC) to a disease-related isoform (PrPSc). Using recombinant human β-PrP, a panel of monoclonal antibodies was produced that efficiently immunoprecipitated native PrPSc and recognized epitopes between residues 93–105, indicating for the first time that this region is exposed in both human vCJD and mouse RML prions. In contrast, monoclonal antibodies raised to human α-PrP were more efficient in immunoprecipitating PrPC than PrPSc, and some of them could also distinguish between different PrP glycoforms. Using these monoclonal antibodies, the physical association of PrP glycoforms was studied in normal brain and in the brains of humans and mice with prion disease. It was shown that while PrPC glycoforms can be selectively immunoprecipitated, the differentially glycosylated molecules of native PrPSc are closely associated and always immunoprecipitate together. Furthermore, the ratio of glycoforms comprising immunoprecipitated native PrPSc from diverse prion strains was similar to those observed on denaturing Western blots. These studies are consistent with the view that the proportion of each glycoform incorporated into PrPSc is probably controlled in a strain-specific manner and that each PrPSc particle contains a mixture of glycoforms.

scholarly journals Familial prion disease-related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM

2021 ◽  
Author(s):  
Li-Qiang Wang ◽  
Kun Zhao ◽  
Han-Ye Yuan ◽  
Xiang-Ning Li ◽  
Hai-Bin Dang ◽  
...  
Keyword(s):  
Amyloid Fibril ◽  
Prion Diseases ◽  
Conformational Stability ◽  
Salt Bridges ◽  
Wild Type ◽  
Left Handed ◽  
Prion Strains ◽  
Fibril Structure ◽  
Clinical Syndromes ◽  
Jakob Disease

Prion diseases are caused by the conformational conversion of prion protein (PrP) from its cellular form (PrPC) into a protease-resistant, aggregated form (PrPSc). 42 different familial mutations were identified in human PrP, which lead to genetic prion diseases with distinct clinical syndromes. Here we report cryo-EM structure of an amyloid fibril formed by full-length human PrP with E196K mutation, a familial Creutzfeldt-Jakob disease-related mutation. This mutation disrupts key interactions in wild-type PrP fibril and results in a rearrangement of the overall structure, forming an amyloid fibril with a conformation distinct from wild-type PrP fibril. The E196K fibril consists of two protofibrils intertwined into a left-handed helix. Each subunit forms five β-strands stabilized by a disulfide bond and an unusual hydrophilic cavity. Two pairs of amino acids (Lys194 and Glu207; Lys196 and Glu200) from opposing subunits form four salt bridges to stabilize the zigzag interface of the two protofibrils. Furthermore, the E196K fibril exhibits a significantly lower conformational stability and protease resistance activity than the wild-type fibril. Our results provide direct structural evidences of the diverse mammalian prion strains and fibril polymorphism of PrP, and highlight the importance of familial mutations in determining the different prion strains.

scholarly journals Human Herpesvirus-6 and -7 in the Brain Microenvironment of Persons with Neurological Pathology and Healthy People

2021 ◽  
Vol 22 (5) ◽  
pp. 2364
Author(s):  
Sandra Skuja ◽  
Simons Svirskis ◽  
Modra Murovska
Keyword(s):  
Neurological Diseases ◽  
Clinical Manifestations ◽  
Disease Process ◽  
Human Herpesvirus ◽  
Antigen Expression ◽  
Brain Regions ◽  
Cell Tropism ◽  
The Central Nervous System ◽  
Cellular Immune ◽  
Neurological Pathology

During persistent human beta-herpesvirus (HHV) infection, clinical manifestations may not appear. However, the lifelong influence of HHV is often associated with pathological changes in the central nervous system. Herein, we evaluated possible associations between immunoexpression of HHV-6, -7, and cellular immune response across different brain regions. The study aimed to explore HHV-6, -7 infection within the cortical lobes in cases of unspecified encephalopathy (UEP) and nonpathological conditions. We confirmed the presence of viral DNA by nPCR and viral antigens by immunohistochemistry. Overall, we have shown a significant increase (p < 0.001) of HHV antigen expression, especially HHV-7 in the temporal gray matter. Although HHV-infected neurons were found notably in the case of HHV-7, our observations suggest that higher (p < 0.001) cell tropism is associated with glial and endothelial cells in both UEP group and controls. HHV-6, predominantly detected in oligodendrocytes (p < 0.001), and HHV-7, predominantly detected in both astrocytes and oligodendrocytes (p < 0.001), exhibit varying effects on neural homeostasis. This indicates a high number (p < 0.001) of activated microglia observed in the temporal lobe in the UEP group. The question remains of whether human HHV contributes to neurological diseases or are markers for some aspect of the disease process.

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