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 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.

Integrating high-throughput genetics and neuroimaging technologies promises greater information on neurobiological anomalies in neurodegenerative diseases

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Diseases ◽  
High Throughput ◽  
Morphological Changes ◽  
Brain Area ◽  
Temporal Distribution ◽  
Brain Regions ◽  
Brain Morphology ◽  
Expression Data ◽  
Imaging Research

The integration of high-throughput genomics and neuroimaging technology has the promise of providing more information about neurobiological irregularities in neurodegenerative illnesses. Transcriptomics-derived connections provide insight into the molecular trajectory of neurodegeneration, prioritizing particular systems and networks while also considering other aspects, including neuropathology and cognition. Causal links between gene expression and brain morphology are unknown, however. If omics systems have a wide impact upstream, they can influence morphological changes identified by MRI. Gene expression is a signal indicating a process already underway in a diseased brain area if it is downstream of structural brain changes. More study on people in the early stages of disease may give insights into the temporal connection between anatomical and expression problems.One such thought is molecular stereotactic propagation. Changes in gene expression may travel across the brain, according to this notion, through tractography trails. They follow the successive pattern of afflicted regions and the temporal distribution of sensitive locations. In addition, cell motility genes are often overexpressed in vulnerable locations. On the other hand, the data on gene expression and its relevance to structural change propagation is still conflicting. The role of immunological processes and motility-related genes in neurodegeneration appears to be validated by expression data.There are no therapies available for neurodegenerative diseases. Symptom development and diagnosis is often delayed due to advanced MRI and clinical stages. Early diagnosis is crucial since therapy interventions should ideally aim at commencing pathogenic processes as soon as possible to avoid the onset of disease and restrict the course of disease. This requires dependable neurodegenerative biomarkers with diagnostic validity. Unfortunately, transcriptomics still has several important limitations. There is a paucity of high-quality expression data encompassing a large number of brain regions, expression data generally collected from healthy persons, comparisons with neuroimaging data from degenerative cohorts, and a lack of consistent approach for transcriptional imaging research. By overcoming this barrier, researchers can uncover prodromal stages of neurodegeneration and therapeutic molecular targets.

scholarly journals Goats naturally devoid of PrPC are resistant to scrapie

2020 ◽  
Vol 51 (1) ◽  
Author(s):  
Øyvind Salvesen ◽  
Arild Espenes ◽  
Malin R. Reiten ◽  
Tram T. Vuong ◽  
Giulia Malachin ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Clinical Signs ◽  
Brain Regions ◽  
Post Inoculation ◽  
Dairy Goats ◽  
Peripheral Tissues ◽  
Clinical Onset ◽  
Natural Mutation

AbstractPrion diseases are progressive and fatal, neurodegenerative disorders described in humans and animals. According to the “protein-only” hypothesis, the normal host-encoded prion protein (PrPC) is converted into a pathological and infectious form (PrPSc) in these diseases. Transgenic knockout models have shown that PrPC is a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene (PRNP) effectively blocks PrPC synthesis. We inoculated 12 goats (4 PRNP+/+, 4 PRNP+/Ter, and 4 PRNPTer/Ter) intracerebrally with goat scrapie prions. The mean incubation time until clinical signs of prion disease was 601 days post-inoculation (dpi) in PRNP+/+ goats and 773 dpi in PRNP+/Ter goats. PrPSc and vacuolation were similarly distributed in the central nervous system (CNS) of both groups and observed in all brain regions and segments of the spinal cord. Generally, accumulation of PrPSc was limited in peripheral organs, but all PRNP+/+ goats and 1 of 4 PRNP+/Ter goats were positive in head lymph nodes. The four PRNPTer/Ter goats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrPSc was observed in the CNS or peripheral tissues of this group, as assessed by immunohistochemistry, enzyme immunoassay, and real-time quaking-induced conversion. Our study shows for the first time that animals devoid of PrPC due to a natural mutation do not propagate prions and are resistant to scrapie. Clinical onset of disease is delayed in heterozygous goats expressing about 50% of PrPC levels.

Developmental influence of the cellular prion protein on the gene expression profile in mouse hippocampus

2011 ◽  
Vol 43 (12) ◽  
pp. 711-725 ◽  
Author(s):  
Stefano Benvegnù ◽  
Paola Roncaglia ◽  
Federica Agostini ◽  
Cristina Casalone ◽  
Cristiano Corona ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Prion Protein ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Prion Diseases ◽  
Physiological Role ◽  
Nervous System Development ◽  
Cellular Prion Protein ◽  
Prion Infection

The conversion of the cellular prion protein (PrPC) to an abnormal and protease-resistant isoform is the key event in prion diseases. Mice lacking PrPC are resistant to prion infection, and downregulation of PrPC during prion infection prevents neuronal loss and the progression to clinical disease. These results are suggestive of the potential beneficial effect of silencing PrPC during prion diseases. However, the silencing of a protein that is widely expressed throughout the central nervous system could be detrimental to brain homeostasis. The physiological role of PrPC remains still unclear, but several putative functions (e.g., neuronal development and maintenance) have been proposed. To assess the influence of PrPC on gene expression profile in the mouse brain, we undertook a microarray analysis by using RNA isolated from the hippocampus at two different developmental stages: newborn (4.5-day-old) and adult (3-mo-old) mice, both from wild-type and Prnp0/0 animals. Comparing the different datasets allowed us to identify “commonly” co-regulated genes and “uniquely” deregulated genes during postnatal development. The absence of PrPC affected several biological pathways, the most representative being cell signaling, cell-cell communication and transduction processes, calcium homeostasis, nervous system development, synaptic transmission, and cell adhesion. However, there was only a moderate alteration of the gene expression profile in our animal models. PrPC deficiency did not lead to a dramatic alteration of gene expression profile and produced moderately altered gene expression levels from young to adult animals. Thus, our results may provide additional support to silencing endogenous PrPC levels as therapeutic approach to prion diseases.

scholarly journals Genome-wide transcriptomics identifies an early preclinical signature of prion infection

2020 ◽  
Author(s):  
Silvia Sorce ◽  
Mario Nuvolone ◽  
Giancarlo Russo ◽  
Andra Chincisan ◽  
Daniel Heinzer ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Prion Diseases ◽  
Clinical Signs ◽  
Mrna Abundance ◽  
Terminal Phase ◽  
Post Inoculation ◽  
Prion Infection ◽  
Molecular Events ◽  
Long Latency ◽  
Genome Wide

The clinical course of prion diseases is accurately predictable despite long latency periods, suggesting that prion pathogenesis is driven by precisely timed molecular events. We constructed a searchable genome-wide atlas of mRNA abundance, splicing and editing alterations during the course of disease in prion-inoculated mice. Prion infection induced transient changes in mRNA abundance and processing already at eight weeks post inoculation, well ahead of any neuropathological and clinical signs. In contrast, microglia-enriched genes displayed an increase simultaneous with the appearance of clinical symptoms, whereas neuronal-enriched transcripts remained unchanged until the very terminal stage of disease. This suggests that glial pathophysiology, rather than neuronal demise, represents the final driver of disease. The administration of young plasma attenuated the occurrence of early mRNA abundance alterations and delayed symptoms in the terminal phase of the disease. The early onset of prion-induced molecular changes might thus point to novel biomarkers and potential interventional targets.

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 Region-Specific Sialylation Pattern of Prion Strains Provides Novel Insight into Prion Neurotropism

2020 ◽  
Vol 21 (3) ◽  
pp. 828 ◽  
Author(s):  
Natallia Makarava ◽  
Jennifer Chen-Yu Chang ◽  
Ilia V. Baskakov
Keyword(s):  
Molecular Mechanisms ◽  
Selective Vulnerability ◽  
Brain Regions ◽  
Dependent Manner ◽  
Infectious Agents ◽  
Prion Infection ◽  
Prion Strains ◽  
Mammalian Prions ◽  
Insight Into ◽  
Host Brain

Mammalian prions are unconventional infectious agents that invade and replicate in an organism by recruiting a normal form of a prion protein (PrPC) and converting it into misfolded, disease-associated state referred to as PrPSc. PrPC is posttranslationally modified with two N-linked glycans. Prion strains replicate by selecting substrates from a large pool of PrPC sialoglycoforms expressed by a host. Brain regions have different vulnerability to prion infection, however, molecular mechanisms underlying selective vulnerability is not well understood. Toward addressing this question, the current study looked into a possibility that sialylation of PrPSc might be involved in defining selective vulnerability of brain regions. The current work found that in 22L -infected animals, PrPSc is indeed sialylated in a region dependent manner. PrPSc in hippocampus and cortex was more sialylated than PrPSc from thalamus and stem. Similar trends were also observed in brain materials from RML- and ME7-infected animals. The current study established that PrPSc sialylation status is indeed region-specific. Together with previous studies demonstrating that low sialylation status accelerates prion replication, this work suggests that high vulnerability of certain brain region to prion infection could be attributed to their low sialylation status.

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