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.

Prion disease

2018 ◽  
Author(s):  
Richard Knight
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Human Diseases ◽  
Brain Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Structural Form ◽  
Spongiform Encephalopathies ◽  
Spongiform Change ◽  
Neurodegenerative Pathology

Prion diseases (also known as transmissible spongiform encephalopathies (TSEs)) affect animals and humans, although only the human diseases will be discussed in this chapter. Despite TSEs having somewhat disparate causes and effects, there are unifying features: TSEs are brain diseases with neurodegenerative pathology, which is typically associated with spongiform change, and, most characteristically, there is tissue deposition of an abnormal structural form of the prion protein. Some of the TSEs are naturally acquired infections and, while others are not, they are potentially transmissible in certain circumstances.

Trace elements and prion diseases: a review of the interactions of copper, manganese and zinc with the prion protein

2006 ◽  
Vol 7 (1-2) ◽  
pp. 97-105 ◽  
Author(s):  
Scott P. Leach ◽  
M. D. Salman ◽  
Dwayne Hamar
Keyword(s):  
Trace Elements ◽  
Prion Protein ◽  
Copper Ions ◽  
Prion Diseases ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Copper Binding ◽  
Spongiform Encephalopathies ◽  
Copper Manganese ◽  
The Brain

Transmissible spongiform encephalopathies (TSEs) are a family of neurodegenerative diseases characterized by their long incubation periods, progressive neurological changes, and spongiform appearance in the brain. There is much evidence to show that TSEs are caused by an isoform of the normal cellular surface prion protein PrPC. The normal function of PrPC is still unknown, but it exhibits properties of a cupro-protein, capable of binding up to six copper ions. There are two differing views on copper's role in prion diseases. While one view looks at the PrPC copper-binding as the trigger for conversion to PrPSc, the opposing viewpoint sees a lack of PrPC copper-binding resulting in the conformational change into the disease causing isoform. Manganese and zinc have been shown to interact with PrPC as well and have been found in abnormal levels in prion diseases. This review addresses the interaction between select trace elements and the PrPC.

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 Prion disease and endoplasmic reticulum stress pathway correlations and treatment pursuits

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Tarah Satterfield ◽  
Jessica Pritchett ◽  
Sarah Cruz ◽  
Kyeorda Kemp
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Protein Accumulation ◽  
Spongiform Encephalopathies ◽  
Unfolded Protein

AbstractBackground: Transmissible spongiform encephalopathies are a collection of rare neurodegenerative disorders characterized by loss of neuronal cells, astrocytosis, and plaque formation. The causative agent of these diseases is thought to be abnormally folded prions and is characterized by a conformational change from normal, cellular prion protein (PrPc) to the abnormal form (PrPTSE). Although, there is evidence that normal prion protein can contribute to these disorders. The unfolded protein response, a conserved series of pathways involved in resolving stress associated with unfolded protein accumulation in the Endoplasmic Reticulum (ER), has been shown to play a role in regulating the development of prion diseases. Methods: This review chose papers based on their relevance to current studies involved in prion protein synthesis and transformation, identifies various links between prion diseases and ER stress, and reports on current and potential treatments as they relate to ER stress and prion diseases. Conclusion: For the advancement of prion disease treatment, it is important to understand the mechanisms involved in prion formation, and ER stress is implicated in prion disease progression. Therefore, targeting the ER or pathways involved in response to stress in the ER may help us treat prion 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.

Human Prion Diseases

2018 ◽  
pp. 159-171
Author(s):  
James W. Ironside
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Human Prion Disease ◽  
Clinical Genetic ◽  
Jakob Disease ◽  
Biochemical Approach ◽  
Protein Isoform ◽  
The Brain

Human prion diseases include idiopathic, genetic, and acquired disorders. Heterogeneous clinicopathologic features make diagnosis challenging. Accurate diagnosis requires a combined clinical, neuropathologic, genetic, and biochemical approach. Neuropathologic assessment is performed following autopsy in most cases. The brain is sampled and studied by tinctorial stains and immunohistochemistry for disease-associated form of the prion protein. Unfixed frozen brain tissue is retained for Western blot analysis of protease-resistant prion protein isoform and for DNA extraction to sequence the prion protein gene. Assessment of spongiform change, gliosis neuronal loss, and accumulation of disease-associated prion protein in the brain can help to determine major categories of human prion disease. Additional clinical, genetic, and biochemical data allow diagnosis and subclassification into disease subtypes, particularly in sporadic Creutzfeldt–Jakob disease. Neuropathology continues to play a role in the recognition and understanding of the expanding spectrum of human prion disease and identification of disease variants that may emerge in the future.

Human prion diseases

2010 ◽  
pp. 5023-5032
Author(s):  
R G Will
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Mammalian Species ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Neuronal Dysfunction ◽  
Spongiform Encephalopathies ◽  
Protease Digestion ◽  
Incubation Periods ◽  
The Brain

Prion protein (for proteinacious infectious particle) is a membrane-associated glycoprotein present in all mammalian species. Its normal function is unknown, but in prion diseases (also known as transmissible spongiform encephalopathies) a post-translationally modified form of the protein, partially resistant to protease digestion, is deposited in the brain and associated—after long incubation periods—with neuronal dysfunction and death....

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

scholarly journals Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant

2021 ◽  
Vol 15 (1) ◽  
pp. 193-196
Author(s):  
Máximo Sanz-Hernández ◽  
Alfonso De Simone
Keyword(s):  
Prion Protein ◽  
Nmr Assignments ◽  
Chemical Shifts ◽  
Prion Diseases ◽  
Random Coil ◽  
Transmissible Spongiform Encephalopathies ◽  
Globular Domain ◽  
Structural Elements ◽  
Spongiform Encephalopathies ◽  
Human Prion Protein

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

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