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.

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.

scholarly journals Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1421-1434 ◽  
Author(s):  
CLAUDIA P. FIGUEIREDO ◽  
NATALIA C. FERREIRA ◽  
GISELLE F. PASSOS ◽  
ROBSON DA COSTA ◽  
FERNANDA S. NEVES ◽  
...  
Keyword(s):  
Prion Protein ◽  
Aromatic Compounds ◽  
Prion Diseases ◽  
Intraperitoneal Administration ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Toxicological Evaluation ◽  
Spongiform Encephalopathies

An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.

scholarly journals New inhibitors of prion replication that target the amyloid precursor

2009 ◽  
Vol 90 (5) ◽  
pp. 1294-1301 ◽  
Author(s):  
Mathieu Charvériat ◽  
Marlène Reboul ◽  
Qian Wang ◽  
Christèle Picoli ◽  
Natacha Lenuzza ◽  
...  
Keyword(s):  
Protein Stability ◽  
Prion Protein ◽  
Prion Diseases ◽  
Direct Interaction ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Regulatory Pathways ◽  
Erythromycin A

At present, there is no effective therapy for any of the neurodegenerative amyloidoses, despite renewed efforts to identify compounds active against the various implicated pathogenetic molecules. We have screened a library of 2960 natural and synthetic compounds in two cell lines chronically infected with mouse prions, and have identified eight new inhibitors of prion replication in vitro. They belong to two distinct chemical families that have not previously been recognised as effective in the field of transmissible spongiform encephalopathies: seven are 3-aminosteroids and one is a derivative of erythromycin A with an oxime functionality. Our results suggest that these aminosteroids inhibit prion replication by triggering a common target, possibly implicated in the regulatory pathways of cellular prion protein metabolism. Furthermore, using a quantitative approach for the study of protein stability, it was shown that the erythromycin A derivative altered prion protein stability by direct interaction. Such direct targeting of this amyloid precursor might provide new clues for the understanding of prion diseases and, more importantly, help to define new molecules that are active against 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.

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.

scholarly journals The Prion Protein Octarepeat Domain Forms Transient β-sheet Structures Upon Residue-Specific Cu(II) and Zn(II) Binding

2021 ◽  
Author(s):  
Maciej Gielnik ◽  
Aneta Szymanska ◽  
Xiaolin Dong ◽  
Jyri Jarvet ◽  
Zeljko M. Svedruzic ◽  
...  
Keyword(s):  
Metal Ions ◽  
Prion Protein ◽  
Metal Binding ◽  
Cd Spectroscopy ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Amyloid Formation ◽  
Spectroscopy Data ◽  
Spongiform Encephalopathies ◽  
Β Sheet

Misfolding of the cellular prion protein (PrPC) is associated with the development of fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). Metal ions appear to play a crucial role in the protein misfolding, and metal imbalance may be part of TSE pathologies. PrPC is a combined Cu(II) and Zn(II) metal binding protein, where the main metal binding site is located in the octarepeat (OR) region. Here, we used biophysical methods to characterize Cu(II) and Zn(II) binding to the isolated OR region. Circular dichroism (CD) spectroscopy data suggest that the OR domain binds up to four Cu(II) ions or two Zn(II) ions. Upon metal binding, the OR region seems to adopt a transient antiparallel β-sheet hairpin structure. Fluorescence spectroscopy data indicates that under neutral conditions, the OR region can bind both Cu(II) and Zn(II) ions, whereas under acidic conditions it binds only Cu(II) ions. Molecular dynamics simulations suggest that binding of both metal ions to the OR region results in formation of β-hairpin structures. As formation of β-sheet structures is a first step towards amyloid formation, we propose that high concentrations of either Cu(II) or Zn(II) ions may have a pro-amyloid effect in TSEs.

scholarly journals Prion protein and prion disease at a glance

2021 ◽  
Vol 134 (17) ◽  
Author(s):  
Caihong Zhu ◽  
Adriano Aguzzi
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Future Studies ◽  
Associated Proteins ◽  
Main Component ◽  
Conformational Conversion

ABSTRACT Prion diseases are neurodegenerative disorders caused by conformational conversion of the cellular prion protein (PrPC) into scrapie prion protein (PrPSc). As the main component of prion, PrPSc acts as an infectious template that recruits and converts normal cellular PrPC into its pathogenic, misfolded isoform. Intriguingly, the phenomenon of prionoid, or prion-like, spread has also been observed in many other disease-associated proteins, such as amyloid β (Aβ), tau and α-synuclein. This Cell Science at a Glance and the accompanying poster highlight recently described physiological roles of prion protein and the advanced understanding of pathogenesis of prion disease they have afforded. Importantly, prion protein may also be involved in the pathogenesis of other neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therapeutic studies of prion disease have also exploited novel strategies to combat these devastating diseases. Future studies on prion protein and prion disease will deepen our understanding of the pathogenesis of a broad spectrum of neurodegenerative conditions.

scholarly journals Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maciej Gielnik ◽  
Michał Taube ◽  
Lilia Zhukova ◽  
Igor Zhukov ◽  
Sebastian K. T. S. Wärmländer ◽  
...  
Keyword(s):  
Prion Protein ◽  
Metal Ion ◽  
Structural Transition ◽  
Cellular Prion Protein ◽  
Zinc Homeostasis ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Structural Conversion ◽  
Protein Size ◽  
Dynamics Simulations

AbstractThe cellular prion protein (PrPC) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrPC can undergo a structural transition into a toxic, β-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrPC binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrPC and Zn(II) ions. Binding of a single Zn(II) ion to the PrPC N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal α-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrPC can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrPC.

scholarly journals Do Bovine Lymphocytes Express a Peculiar Prion Protein?

2002 ◽  
Vol 9 (4) ◽  
pp. 245-252 ◽  
Author(s):  
France Mélot ◽  
Caroline Thielen ◽  
Thouraya Labiet ◽  
Sabine Eisher ◽  
Olivier Jolois ◽  
...  
Keyword(s):  
Prion Protein ◽  
Immune Cells ◽  
Surface Protein ◽  
In Vitro Study ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Lymphoid Tissues ◽  
Spongiform Encephalopathies ◽  
Bovine Lymphocytes

The cellular prion protein (PrPc) is a glycolipid-anchored cell surface protein that usually exhibits three glycosylation states. Its post-translationally modified isoform, PrPsc, is involved in the pathogenesis of various transmissible spongiform encephalopathies (TSEs). In bovine species, BSE infectivity appears to be restricted to the central nervous system; few or no detectable infectivity is found in lymphoid tissues in contrast to scrapie or variant CJD. Since expression of PrPc is a prerequisite for prion replication, we have investigated PrPc expression by bovine immune cells. Lymphocytes from blood and five different lymph organs were isolated from the same animal to assess intra- and interindividual variability of PrPc expression, considering six individuals. As shown by flow cytometry, this expression is absent or weak on granulocytes but is measurable on monocytes, B and T cells from blood and lymph organs. The activation of the bovine cells produces an upregulation of PrPc. The results of our in vitro study of PrPc biosynthesis are consistent with previous studies in other species. Interestingly, western blotting experiments showed only one form of the protein, the diglycosylated band. We propose that the glycosylation state could explain the lack of infectivity of the bovine immune cells.

Prions: Protein Aggregation and Infectious Diseases

2009 ◽  
Vol 89 (4) ◽  
pp. 1105-1152 ◽  
Author(s):  
Adriano Aguzzi ◽  
Anna Maria Calella
Keyword(s):  
Protein Aggregation ◽  
Prion Diseases ◽  
Physiological Role ◽  
Infectious Agent ◽  
Normal Function ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Pathological Features ◽  
Spongiform Encephalopathies

Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrPC) of the host. PrPCis necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrPC, and therefore, understanding the physiological role of PrPCmay help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics.

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