scholarly journals Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

2021 ◽  
Author(s):  
Luise Linsenmeier ◽  
Behnam Mohammadi ◽  
Mohsin Shafiq ◽  
Karl Frontzek ◽  
Julia Baer ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Protein Misfolding ◽  
Therapeutic Potential ◽  
Prion Diseases ◽  
Neuronal Cell ◽  
Cellular Prion Protein ◽  
Protective Mechanism ◽  
Neuroprotective Effects ◽  
Binding Characteristics

The cellular prion protein (PrPC) is a central player in neurodegenerative diseases caused by protein misfolding, such as prion diseases or Alzheimer's disease (AD). Expression levels of this GPI-anchored glycoprotein, especially at the neuronal cell surface, critically correlate with various pathomechanistic aspects underlying these diseases, such as templated misfolding (in prion diseases) and neurotoxicity and, hence, with disease progression and severity. In stark contrast to cell-associated PrPC, soluble extracellular forms or fragments of PrP are linked with neuroprotective effects, which is likely due to their ability to interfere with neurotoxic disease-associated protein conformers in the interstitial fluid. Fittingly, the endogenous proteolytic release of PrPC by the metalloprotease ADAM10 ('shedding') was characterized as a protective mechanism. Here, using a recently generated cleavage-site specific antibody, we shed new light on earlier studies by demonstrating that shed PrP (sPrP) negatively correlates with conformational conversion (in prion disease) and is markedly redistributed in murine brain in the presence of prion deposits or AD-associated amyloid plaques indicating a blocking and sequestrating activity. Importantly, we reveal that administration of certain PrP-directed antibodies and other ligands results in increased PrP shedding in cells and organotypic brain slice cultures. We also provide mechanistic and structural insight into this shedding-stimulating effect. In addition, we identified a striking exception to this, as one particular neuroprotective antibody, due to its special binding characteristics, did not cause increased shedding but rather strong surface clustering followed by fast endocytosis and degradation of PrPC. Both mechanisms may contribute to the beneficial action described for some PrP-directed antibodies/ligands and pave the way for new therapeutic strategies against devastating and currently incurable neurodegenerative 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 Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hideyuki Hara ◽  
Junji Chida ◽  
Keiji Uchiyama ◽  
Agriani Dini Pasiana ◽  
Etsuhisa Takahashi ◽  
...  
Keyword(s):  
Prion Protein ◽  
Influenza A Virus ◽  
Protein Misfolding ◽  
Influenza A ◽  
Prion Diseases ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Infected Cells ◽  
Hit And Run

AbstractMisfolding of the cellular prion protein, PrPC, into the amyloidogenic isoform, PrPSc, which forms infectious protein aggregates, the so-called prions, is a key pathogenic event in prion diseases. No pathogens other than prions have been identified to induce misfolding of PrPC into PrPSc and propagate infectious prions in infected cells. Here, we found that infection with a neurotropic influenza A virus strain (IAV/WSN) caused misfolding of PrPC into PrPSc and generated infectious prions in mouse neuroblastoma cells through a hit-and-run mechanism. The structural and biochemical characteristics of IAV/WSN-induced PrPSc were different from those of RML and 22L laboratory prions-evoked PrPSc, and the pathogenicity of IAV/WSN-induced prions were also different from that of RML and 22L prions, suggesting IAV/WSN-specific formation of PrPSc and infectious prions. Our current results may open a new avenue for the role of viral infection in misfolding of PrPC into PrPSc and formation of infectious prions.

scholarly journals Decrease in Skin Prion-Seeding Activity of Prion-Infected Mice Treated with a Compound Against Human and Animal Prions: a First Possible Biomarker for Prion Therapeutics

2021 ◽  
Author(s):  
Mingxuan Ding ◽  
Kenta Teruya ◽  
Weiguanliu Zhang ◽  
Hae Weon Lee ◽  
Jue Yuan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Prion Protein ◽  
Therapeutic Efficacy ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Inhibitory Effect ◽  
Cellular Prion Protein ◽  
Cellulose Ethers ◽  
Wasting Disease

AbstractPrevious studies have revealed that the infectious scrapie isoform of prion protein (PrPSc) harbored in the skin tissue of patients or animals with prion diseases can be amplified and detected through the serial protein misfolding cyclic amplification (sPMCA) or real-time quaking-induced conversion (RT-QuIC) assays. These findings suggest that skin PrPSc-seeding activity may serve as a biomarker for the diagnosis of prion diseases; however, its utility as a biomarker for prion therapeutics remains largely unknown. Cellulose ethers (CEs, such as TC-5RW), widely used as food and pharmaceutical additives, have recently been shown to prolong the lifespan of prion-infected mice and hamsters. Here we report that in transgenic (Tg) mice expressing hamster cellular prion protein (PrPC) infected with the 263K prion, the prion-seeding activity becomes undetectable in the skin tissues of TC-5RW-treated Tg mice by both sPMCA and RT-QuIC assays, whereas such prion-seeding activity is readily detectable in the skin of untreated mice. Notably, TC-5RW exhibits an inhibitory effect on the in vitro amplification of PrPSc in both skin and brain tissues by sPMCA and RT-QuIC. Moreover, we reveal that TC-5RW is able to directly decrease protease-resistant PrPSc and inhibit the seeding activity of PrPSc from chronic wasting disease and various human prion diseases. Our results suggest that the level of prion-seeding activity in the skin may serve as a useful biomarker for assessing the therapeutic efficacy of compounds in a clinical trial of prion diseases and that TC-5RW may have the potential for the prevention/treatment of human prion diseases.

scholarly journals Comparative analysis of heparin affecting the biochemical properties of chicken and murine prion proteins

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247248
Author(s):  
Li-Juan Wang ◽  
Xiao-Dan Gu ◽  
Xiao-Xiao Li ◽  
Liang Shen ◽  
Hong-Fang Ji
Keyword(s):  
Prion Protein ◽  
Conformational Changes ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Mammalian Species ◽  
Biochemical Properties ◽  
Cellular Prion Protein ◽  
Great Loss ◽  
Heparin Concentration ◽  
Β Sheet

The conversion of cellular prion protein (PrPC) to disease-provoking conformer (PrPSc) is crucial in the pathogenesis of prion diseases. Heparin has been shown to enhance mammalian prion protein misfolding. As spontaneous prion disease has not been reported in non-mammalian species, such as chicken, it is interesting to explore the influence of heparin on the conversion of chicken prion protein (ChPrP). Herein, we investigated the influences of heparin on biochemical properties of full-length recombinant ChPrP, with murine prion protein (MoPrP) as control. The results showed that at low heparin concentration (10 μg/mL), a great loss of solubility was observed for both MoPrP and ChPrP using solubility assays. In contrast, when the concentration of heparin was high (30 μg/mL), the solubility of MoPrP and ChPrP both decreased slightly. Using circular dichroism, PK digestion and transmission electron microscopy, significantly increased β-sheet content, PK resistance and size of aggregates were observed for MoPrP interacted with 30 μg/mL heparin, whereas 30 μg/mL heparin-treated ChPrP showed less PK resistance and slight increase of β-sheet structure. Therefore, heparin can induce conformational changes in both MoPrP and ChPrP and the biochemical properties of the aggregates induced by heparin could be modified by heparin concentration. These results highlight the importance of concentration of cofactors affecting PrP misfolding.

scholarly journals Porcine Prion Protein as a Paradigm of Limited Susceptibility to Prion Strain Propagation

2020 ◽  
Author(s):  
Juan Carlos Espinosa ◽  
Alba Marín-Moreno ◽  
Patricia Aguilar-Calvo ◽  
Sylvie L Benestad ◽  
Olivier Andreoletti ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Conformational Flexibility ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Prion Strain ◽  
Experimental Transmission ◽  
Prion Strains ◽  
Jakob Disease

Abstract Although experimental transmission of bovine spongiform encephalopathy (BSE) to pigs and transgenic mice expressing pig cellular prion protein (PrPC) (porcine PrP [PoPrP]–Tg001) has been described, no natural cases of prion diseases in pig were reported. This study analyzed pig-PrPC susceptibility to different prion strains using PoPrP-Tg001 mice either as animal bioassay or as substrate for protein misfolding cyclic amplification (PMCA). A panel of isolates representatives of different prion strains was selected, including classic and atypical/Nor98 scrapie, atypical-BSE, rodent scrapie, human Creutzfeldt-Jakob-disease and classic BSE from different species. Bioassay proved that PoPrP-Tg001-mice were susceptible only to the classic BSE agent, and PMCA results indicate that only classic BSE can convert pig-PrPC into scrapie-type PrP (PrPSc), independently of the species origin. Therefore, conformational flexibility constraints associated with pig-PrP would limit the number of permissible PrPSc conformations compatible with pig-PrPC, thus suggesting that pig-PrPC may constitute a paradigm of low conformational flexibility that could confer high resistance to the diversity of prion strains.

scholarly journals Extracellular vesicles – propagators of neuropathology and sources of potential biomarkers and therapeutics for neurodegenerative diseases

2020 ◽  
Vol 133 (23) ◽  
pp. jcs243139
Author(s):  
Natasha Vassileff ◽  
Lesley Cheng ◽  
Andrew F. Hill
Keyword(s):  
Neurodegenerative Diseases ◽  
Extracellular Vesicles ◽  
Protein Misfolding ◽  
Therapeutic Potential ◽  
Prion Diseases ◽  
Cellular Communication ◽  
Compensatory Process ◽  
Potential Therapeutics ◽  
Lateral Sclerosis ◽  
Potential Biomarkers

ABSTRACTNeurodegenerative diseases are characterised by the irreversible degeneration of neurons in the central or peripheral nervous systems. These include amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases. Small extracellular vesicles (sEVs), a type of EV involved in cellular communication, have been well documented as propagating neurodegenerative diseases. These sEVs carry cargo, such as proteins and RNA, to recipient cells but are also capable of promoting protein misfolding, thus actively contributing to the progression of these diseases. sEV secretion is also a compensatory process for lysosomal dysfunction in the affected cells, despite inadvertently propagating disease to recipient cells. Despite this, sEV miRNAs have biomarker potential for the early diagnosis of these diseases, while stem cell-derived sEVs and those generated through exogenous assistance demonstrate the greatest therapeutic potential. This Review will highlight novel advancements in the involvement of sEVs as propagators of neuropathology, biomarkers and potential therapeutics in neurodegenerative diseases.

scholarly journals Melatonin-mediated Calcineurin Inactivation Attenuates Prion Protein-induced Nf-Kb- Driven Pro-Inflammation Response

2021 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Jae-Won Seol ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Autophagic Flux ◽  
Mrna Levels ◽  
Autophagy Flux ◽  
Neuroprotective Effects ◽  
Protein Levels

Abstract Background: Prion diseases are a group of prevalent and rapidly progressive neurodegenerative disorders that lead to chronic inflammation and neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Melatonin has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death.Methods: Real-time quantitative PCR was used to detect mRNA levels of proinflammatory cytokines. Western blot was used to analysis p-nfkb, p-bcl10, calcineurin, prpc and autophagy flux pathway. Immunocytochemistry was used to analysis p-nfkb and calcineurin. Ca2+ levels were measured by fluo-4 using confocal microscope. Calcineurin activity was used to detect with calcineurin cellular activity assay kit. Transmission electron microscopy (TEM) was used to detect autophagy flux.Results: In the present study, we investigated whether melatonin attenuates prion peptide-mediated neuroinflammation and reduces calcineurin. We found that melatonin treatment inhibits prion protein-induced apoptosis. Melatonin inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, melatonin increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and melatonin inhibited prion protein-induced neurotoxicity through autophagy flux inhibition.Conclusions: Taken together, our results illuminate that melatonin attenuated prion protein-induced neurinflammation through calcineurin inactivation and autophagic flux reduction, and also suggest that melatonin may provide effective strategy for therapy against neurodegenerative diseases, including prion diseases.

scholarly journals Neurometals in the Pathogenesis of Prion Diseases

2021 ◽  
Vol 22 (3) ◽  
pp. 1267
Author(s):  
Masahiro Kawahara ◽  
Midori Kato-Negishi ◽  
Ken-ichiro Tanaka
Keyword(s):  
Trace Elements ◽  
Trace Metals ◽  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
New Findings ◽  
Copper Zinc ◽  
Conformational Conversion ◽  
Iron And Manganese

Prion diseases are progressive and transmissive neurodegenerative diseases. The conformational conversion of normal cellular prion protein (PrPC) into abnormal pathogenic prion protein (PrPSc) is critical for its infection and pathogenesis. PrPC possesses the ability to bind to various neurometals, including copper, zinc, iron, and manganese. Moreover, increasing evidence suggests that PrPC plays essential roles in the maintenance of homeostasis of these neurometals in the synapse. In addition, trace metals are critical determinants of the conformational change and toxicity of PrPC. Here, we review our studies and other new findings that inform the current understanding of the links between trace elements and physiological functions of PrPC and the neurotoxicity of PrPSc.

Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

2020 ◽  
Vol 26 ◽  
Author(s):  
Nimra Javaid ◽  
Muhammad Ajmal Shah ◽  
Azhar Rasul ◽  
Zunera Chauhdary ◽  
Uzma Saleem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ellagic Acid ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Acetylcholinesterase Activity ◽  
Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

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