scholarly journals Distribution of microRNA profiles in pre-clinical and clinical forms of murine and human prion disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lesley Cheng ◽  
Camelia Quek ◽  
Xia Li ◽  
Shayne A. Bellingham ◽  
Laura J. Ellett ◽  
...  
Keyword(s):  
Prion Disease ◽  
Molecular Subtype ◽  
Prion Diseases ◽  
Clinical Stage ◽  
Clinical Samples ◽  
Serum Samples ◽  
Prion Infection ◽  
Clinical Forms ◽  
Therapeutic Development ◽  
The Brain

AbstractPrion diseases are distinguished by long pre-clinical incubation periods during which prions actively propagate in the brain and cause neurodegeneration. In the pre-clinical stage, we hypothesize that upon prion infection, transcriptional changes occur that can lead to early neurodegeneration. A longitudinal analysis of miRNAs in pre-clinical and clinical forms of murine prion disease demonstrated dynamic expression changes during disease progression in the affected thalamus region and serum. Serum samples at each timepoint were collected whereby extracellular vesicles (EVs) were isolated and used to identify blood-based biomarkers reflective of pathology in the brain. Differentially expressed EV miRNAs were validated in human clinical samples from patients with human sporadic Creutzfeldt-Jakob disease (sCJD), with the molecular subtype at codon 129 either methionine-methionine (MM, n = 14) or valine-valine (VV, n = 12) compared to controls (n = 20). EV miRNA biomarkers associated with prion infection predicted sCJD with an AUC of 0.800 (85% sensitivity and 66.7% specificity) in a second independent validation cohort (n = 26) of sCJD and control patients with MM or VV subtype. This study discovered clinically relevant miRNAs that benefit diagnostic development to detect prion-related diseases and therapeutic development to inhibit prion infectivity.

scholarly journals Neuroinflammation, Microglia, and Cell-Association during Prion Disease

Viruses ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 65 ◽  
Author(s):  
James Carroll ◽  
Bruce Chesebro
Keyword(s):  
Central Nervous System ◽  
Prion Disease ◽  
Host Defense ◽  
Prion Diseases ◽  
Infectious Agent ◽  
Prion Infection ◽  
Cell Association ◽  
Prion Propagation ◽  
The Central Nervous System ◽  
The Brain

Prion disorders are transmissible diseases caused by a proteinaceous infectious agent that can infect the lymphatic and nervous systems. The clinical features of prion diseases can vary, but common hallmarks in the central nervous system (CNS) are deposition of abnormally folded protease-resistant prion protein (PrPres or PrPSc), astrogliosis, microgliosis, and neurodegeneration. Numerous proinflammatory effectors expressed by astrocytes and microglia are increased in the brain during prion infection, with many of them potentially damaging to neurons when chronically upregulated. Microglia are important first responders to foreign agents and damaged cells in the CNS, but these immune-like cells also serve many essential functions in the healthy CNS. Our current understanding is that microglia are beneficial during prion infection and critical to host defense against prion disease. Studies indicate that reduction of the microglial population accelerates disease and increases PrPSc burden in the CNS. Thus, microglia are unlikely to be a foci of prion propagation in the brain. In contrast, neurons and astrocytes are known to be involved in prion replication and spread. Moreover, certain astrocytes, such as A1 reactive astrocytes, have proven neurotoxic in other neurodegenerative diseases, and thus might also influence the progression of prion-associated neurodegeneration.

scholarly journals Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

Pathogens ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 482
Author(s):  
Simote Foliaki ◽  
Bradley Groveman ◽  
Jue Yuan ◽  
Ryan Walters ◽  
Shulin Zhang ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurological Disorders ◽  
Prion Diseases ◽  
Three Dimensional ◽  
Protein Isoforms ◽  
Genetic Modifiers ◽  
Neuronal Tissue ◽  
Prion Infection ◽  
E200k Mutation

Cerebral organoids (COs) are a self-organizing three-dimensional brain tissue mimicking the human cerebral cortex. COs are a promising new system for modelling pathological features of neurological disorders, including prion diseases. COs expressing normal prion protein (PrPC) are susceptible to prion infection when exposed to the disease isoforms of PrP (PrPD). This causes the COs to develop aspects of prion disease pathology considered hallmarks of disease, including the production of detergent-insoluble, protease-resistant misfolded PrPD species capable of seeding the production of more misfolded species. To determine whether COs can model aspects of familial prion diseases, we produced COs from donor fibroblasts carrying the E200K mutation, the most common cause of human familial prion disease. The mature E200K COs were assessed for the hallmarks of prion disease. We found that up to 12 months post-differentiation, E200K COs harbored no PrPD as confirmed by the absence of detergent-insoluble, protease-resistant, and seeding-active PrP species. Our results suggest that the presence of the E200K mutation within the prion gene is insufficient to cause disease in neuronal tissue. Therefore, other factors, such as further genetic modifiers or aging processes, may influence the onset of misfolding.

scholarly journals Large-scale lipidomic profiling identifies novel potential biomarkers for prion diseases and highlights lipid raft-related pathways

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Yong-Chan Kim ◽  
Junbeom Lee ◽  
Dae-Weon Lee ◽  
Byung-Hoon Jeong
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Large Scale ◽  
Right Hemisphere ◽  
Prion Diseases ◽  
Lipid Extraction ◽  
Transmissible Spongiform Encephalopathies ◽  
Pathway Enrichment Analysis ◽  
The Brain ◽  
Potential Biomarkers

AbstractPrion diseases are transmissible spongiform encephalopathies induced by the abnormally-folded prion protein (PrPSc), which is derived from the normal prion protein (PrPC). Previous studies have reported that lipid rafts play a pivotal role in the conversion of PrPC into PrPSc, and several therapeutic strategies targeting lipids have led to prolonged survival times in prion diseases. In addition, phosphatidylethanolamine, a glycerophospholipid member, accelerated prion disease progression. Although several studies have shown that prion diseases are significantly associated with lipids, lipidomic analyses of prion diseases have not been reported thus far. We intraperitoneally injected phosphate-buffered saline (PBS) or ME7 mouse prions into mice and sacrificed them at different time points (3 and 7 months) post-injection. To detect PrPSc in the mouse brain, we carried out western blotting analysis of the left hemisphere of the brain. To identify potential novel lipid biomarkers, we performed lipid extraction on the right hemisphere of the brain and liquid chromatography mass spectrometry (LC/MS) to analyze the lipidomic profiling between non-infected mice and prion-infected mice. Finally, we analyzed the altered lipid-related pathways by a lipid pathway enrichment analysis (LIPEA). We identified a total of 43 and 75 novel potential biomarkers at 3 and 7 months in prion-infected mice compared to non-infected mice, respectively. Among these novel potential biomarkers, approximately 75% of total lipids are glycerophospholipids. In addition, altered lipids between the non-infected and prion-infected mice were related to sphingolipid, glycerophospholipid and glycosylphosphatidylinositol (GPI)-anchor-related pathways. In the present study, we found novel potential biomarkers and therapeutic targets of prion disease. To the best of our knowledge, this study reports the first large-scale lipidomic profiling in prion diseases.

scholarly journals Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91–106

2020 ◽  
Vol 21 (19) ◽  
pp. 7260
Author(s):  
Keiji Uchiyama ◽  
Hironori Miyata ◽  
Yoshitaka Yamaguchi ◽  
Morikazu Imamura ◽  
Mariya Okazaki ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Dependent Manner ◽  
Prion Infection ◽  
Amplification Assay ◽  
The Brain ◽  
Strain Dependent

Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform, PrPSc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91–106 were generated in the absence of endogenous PrPC, designated Tg(PrP∆91–106)/Prnp0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91–106)/Prnp0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrPSc∆91–106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrPSc∆91–106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrPSc∆91–104 after incubation with BSE-PrPSc-prions but not with RML- and 22L–PrPSc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91–104 into PrPSc∆91–104 even after incubation with RML- and 22L-PrPSc-prions. These results suggest that residues 91–106 or 91–104 of PrPC are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc.

scholarly journals Ethanolamine Is a New Anti-Prion Compound

2021 ◽  
Vol 22 (21) ◽  
pp. 11742
Author(s):  
Keiji Uchiyama ◽  
Hideyuki Hara ◽  
Junji Chida ◽  
Agriani Dini Pasiana ◽  
Morikazu Imamura ◽  
...  
Keyword(s):  
Drinking Water ◽  
Oral Administration ◽  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Mouse Neuroblastoma ◽  
Conformational Conversion ◽  
The Brain ◽  
Cells Cultured

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 PrPSc. PrPSc is produced through conformational conversion of the cellular isoform of prion protein, PrPC, 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 PrPSc levels when cultured in advanced Dulbecco’s modified eagle medium (DMEM) but not in classic DMEM. PrPC 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 PrPSc levels in N2aC24L1-3 cells, but not PrPC 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.

scholarly journals Clinical Laboratory Tests Used To Aid in Diagnosis of Human Prion Disease

2019 ◽  
Vol 57 (10) ◽  
Author(s):  
Allyson Connor ◽  
Han Wang ◽  
Brian S. Appleby ◽  
Daniel D. Rhoads
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Laboratory Testing ◽  
Clinical Laboratory ◽  
Prion Diseases ◽  
Neuron Specific Enolase ◽  
Brain Biopsy ◽  
Alpha Synuclein ◽  
Clinical Laboratory Testing ◽  
The Brain

ABSTRACT Prion diseases are a group of rapidly progressive and always fatal neurodegenerative disorders caused by misfolded prion protein in the brain. Although autopsy remains the gold-standard diagnostic tool, antemortem laboratory testing can be performed to aid in the diagnosis of prion disease. This review is meant to help laboratory directors and physicians in their interpretation of test results. Laboratory assays to detect both nonspecific biomarkers of prion disease and prion-specific biomarkers can be used. The levels of nonspecific biomarkers in cerebrospinal fluid (CSF) are elevated when rapid neurodegeneration is occurring in the patient, and these markers include 14-3-3, tau, neuron-specific enolase, S100B, and alpha-synuclein. These markers have various sensitivities and specificities but are overall limited, as the levels of any of these analytes can be elevated in nonprion disease that is causing rapid damage of brain tissue. Prion-specific assays used in clinical laboratory testing are currently limited to two options. The first option is second-generation real-time quaking-induced conversion (RT-QuIC) performed on CSF, and the second option is Western blotting of a brain biopsy specimen used to detect protease-resistant prion protein. Although both tests have exquisite specificity, RT-QuIC has a sensitivity of 92 to 97.2% in symptomatic individuals, compared to the brain biopsy Western blot sensitivity of 20 to 60%. RT-QuIC was added to the Centers for Disease Control and Prevention’s diagnostic criteria for prion disease in 2018. Other caveats of laboratory testing need to be considered, as sporadic, genetic, and acquired forms of prion disease have different clinical and laboratory presentations, and these caveats are discussed. Laboratory testing plays an important role in the diagnosis of prion disease, which is often challenging to diagnose.

scholarly journals Mitochondrial Respiration Is Impaired during Late-Stage Hamster Prion Infection

2017 ◽  
Vol 91 (18) ◽  
Author(s):  
Robert Faris ◽  
Roger A. Moore ◽  
Anne Ward ◽  
Dan E. Sturdevant ◽  
Suzette A. Priola
Keyword(s):  
Electron Transport ◽  
Transgenic Mice ◽  
Mitochondrial Dysfunction ◽  
Prion Protein ◽  
Prion Disease ◽  
Mitochondrial Respiration ◽  
Brain Mitochondria ◽  
Prion Strain ◽  
Prion Infection ◽  
The Brain

ABSTRACT Mitochondria are crucial to proper neuronal function and overall brain health. Mitochondrial dysfunction within the brain has been observed in many neurodegenerative diseases, including prion disease. Several markers of decreased mitochondrial activity during prion infection have been reported, yet the bioenergetic respiratory status of mitochondria from prion-infected animals is unknown. Here we show that clinically ill transgenic mice overexpressing hamster prion protein (Tg7) infected with the hamster prion strain 263K suffer from a severe deficit in mitochondrial oxygen consumption in response to the respiratory complex II substrate succinate. Characterization of the mitochondrial proteome of purified brain mitochondria from infected and uninfected Tg7 mice showed significant differences in the relative abundance of key mitochondrial electron transport proteins in 263K-infected animals relative to that in controls. Our results suggest that at clinical stages of prion infection, dysregulation of respiratory chain proteins may lead to impairment of mitochondrial respiration in the brain. IMPORTANCE Mitochondrial dysfunction is present in most major neurodegenerative diseases, and some studies have suggested that mitochondrial processes may be altered during prion disease. Here we show that hamster prion-infected transgenic mice overexpressing the hamster prion protein (Tg7 mice) suffer from mitochondrial respiratory deficits. Tg7 mice infected with the 263K hamster prion strain have little or no signs of mitochondrial dysfunction at the disease midpoint but suffer from a severe deficit in mitochondrial respiration at the clinical phase of disease. A proteomic analysis of the isolated brain mitochondria from clinically affected animals showed that several proteins involved in electron transport, mitochondrial dynamics, and mitochondrial protein synthesis were dysregulated. These results suggest that mitochondrial dysfunction, possibly exacerbated by prion protein overexpression, occurs at late stages during 263K prion disease and that this dysfunction may be the result of dysregulation of mitochondrial proteins.

scholarly journals The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

2021 ◽  
Author(s):  
Bei Li ◽  
Meiling Chen ◽  
Adriano Aguzzi ◽  
Caihong Zhu
Keyword(s):  
Disease Progression ◽  
Infected Mouse ◽  
Prion Disease ◽  
Prion Diseases ◽  
Scavenger Receptor ◽  
Amyloid Β ◽  
List Type ◽  
Macrophage Scavenger Receptor ◽  
The Brain

Abstract The progression of prion diseases is accompanied by the accumulation of prions in the brain. Ablation of microglia enhances prion accumulation and accelerates disease progression, suggesting that microglia play a neuroprotective role by clearing prions. However, the mechanisms underlying the phagocytosis and clearance of prion are largely unknown. The macrophage scavenger receptor 1 (Msr1) is an important phagocytic receptor expressed by microglia in the brain and is involved in the uptake and clearance of soluble amyloid-β. We therefore asked whether Msr1 might play a role in prion clearance and assessed the scavenger function of Msr1 in prion pathogenesis. We found that Msr1 expression was upregulated in prion-infected mouse brains. However, Msr1 deficiency did not change prion disease progression or lesion patterns. Prion deposition in Msr1 deficient mice was similar to their wild-type littermates. In addition, prion-induced neuroinflammation was not affected by Msr1 ablation. We conclude that Msr1 does not play a major role in prion pathogenesis. Key messages Msr1 expression is upregulated in prion-infected mouse brains at the terminal stage Msr1 deficiency does not affect prion disease progression Msr1 does not play a major role in prion clearance or prion pathogenesis Microglia-mediated phagocytosis and clearance of Aβ and prion may adopt distinct molecular pathways

scholarly journals Glial activation in prion diseases is strictly nonautonomous and requires neuronal PrPSc

2021 ◽  
Author(s):  
Asvin KK Lakkaraju ◽  
Silvia Sorce ◽  
Assunta Senatore ◽  
Mario Nuvolone ◽  
Jingjing Guo ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Life Span ◽  
Prion Disease ◽  
Neuronal Death ◽  
Prion Diseases ◽  
Clinical Disease ◽  
Molecular Changes ◽  
Prion Infection ◽  
Normal Life Span ◽  
Neural Dysfunction

Although prion infections cause cognitive impairment and neuronal death, transcriptional and translational profiling shows progressive derangement within glia but surprisingly little changes within neurons. Here we expressed PrPC selectively in neurons, astrocytes or oligodendrocytes of mice. After prion infection, both astrocyte and neuron-restricted PrPC expression led to copious brain accumulation of PrPSc. As expected, neuron-restricted expression was associated with typical prion disease. However, mice with astrocyte-restricted PrPC expression experienced a normal life span, did not develop clinical disease, and did not show astro- or microgliosis. Besides confirming that PrPSc is innocuous to PrPC-deficient neurons, these results show that astrocyte-born PrPSc does not activate the extreme neuroinflammation that accompanies the onset of prion disease and precedes any molecular changes of neurons. This points to a nonautonomous mechanism by which prion-infected neurons instruct astrocytes and microglia to acquire a specific cellular state that, in turn, drives neural dysfunction.

scholarly journals Complete microglia deficiency accelerates prion disease without enhancing CNS prion accumulation

2021 ◽  
Author(s):  
Barry M. Bradford ◽  
Lynne I. McGuire ◽  
David A. Hume ◽  
Clare Pridans ◽  
Neil A. Mabbott
Keyword(s):  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Reactive Astrocytes ◽  
Refined Model ◽  
Wild Type ◽  
Unfolded Protein ◽  
The Impact ◽  
The Brain ◽  
Synaptic Pruning

SUMMARYPrion diseases are transmissible, neurodegenerative disorders to which there are no cures. Previous studies show that reduction of microglia accelerates prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. In Csf1rΔFIRE mice, the deletion of an enhancer within Csf1r specifically blocks microglia development, however, their brains develop normally with none of the deficits reported in other microglia-deficient models. Csf1rΔFIRE mice were used as a refined model to study the impact of microglia-deficiency on CNS prion disease. Although Csf1rΔFIRE mice succumbed to prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced synaptic pruning and unfolded protein responses. Our data suggest that rather than engulfing and degrading prions, the microglia instead provide neuroprotection and restrict the harmful activities of reactive astrocytes.

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