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1
Martins, V. R., A. F. Mercadante, A. L. B. Cabral, A. R. O. Freitas, and R. M. R. P. S. Castro. "Insights into the physiological function of cellular prion protein." Brazilian Journal of Medical and Biological Research 34, no. 5 (May 2001): 585–95. http://dx.doi.org/10.1590/s0100-879x2001000500005.
Повний текст джерела
2
Franzmann, Titus M., Marcus Jahnel, Andrei Pozniakovsky, Julia Mahamid, Alex S. Holehouse, Elisabeth Nüske, Doris Richter, et al. "Phase separation of a yeast prion protein promotes cellular fitness." Science 359, no. 6371 (January 4, 2018): eaao5654. http://dx.doi.org/10.1126/science.aao5654.
Повний текст джерелаАнотація:
Despite the important role of prion domains in neurodegenerative disease, their physiological function has remained enigmatic. Previous work with yeast prions has defined prion domains as sequences that form self-propagating aggregates. Here, we uncovered an unexpected function of the canonical yeast prion protein Sup35. In stressed conditions, Sup35 formed protective gels via pH-regulated liquid-like phase separation followed by gelation. Phase separation was mediated by the N-terminal prion domain and regulated by the adjacent pH sensor domain. Phase separation promoted yeast cell survival by rescuing the essential Sup35 translation factor from stress-induced damage. Thus, prion-like domains represent conserved environmental stress sensors that facilitate rapid adaptation in unstable environments by modifying protein phase behavior.
3
Miranzadeh Mahabadi, Hajar, and Changiz Taghibiglou. "Cellular Prion Protein (PrPc): Putative Interacting Partners and Consequences of the Interaction." International Journal of Molecular Sciences 21, no. 19 (September 25, 2020): 7058. http://dx.doi.org/10.3390/ijms21197058.
Повний текст джерелаАнотація:
Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide range of protein partners because of the intrinsically disordered nature of the protein’s N-terminus. Numerous studies have attempted to decipher the physiological role of the prion protein by searching for proteins which interact with PrPc. Biochemical characteristics and biological functions both appear to be affected by interacting protein partners. The key challenge in identifying a potential interacting partner is to demonstrate that binding to a specific ligand is necessary for cellular physiological function or malfunction. In this review, we have summarized the intracellular and extracellular interacting partners of PrPc and potential consequences of their binding. We also briefly describe prion disease-related mutations at the end of this review.
4
Westergard, Laura, Heather M. Christensen, and David A. Harris. "The cellular prion protein (PrPC): Its physiological function and role in disease." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1772, no. 6 (June 2007): 629–44. http://dx.doi.org/10.1016/j.bbadis.2007.02.011.
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5
Yoon, Sungtae, Gyeongyun Go, Yeomin Yoon, Jiho Lim, Gaeun Lee, and Sanghun Lee. "Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases." Biomolecules 11, no. 6 (May 22, 2021): 784. http://dx.doi.org/10.3390/biom11060784.
Повний текст джерелаАнотація:
A cellular prion protein (PrPC) is a ubiquitous cell surface glycoprotein, and its physiological functions have been receiving increased attention. Endogenous PrPC is present in various kidney tissues and undergoes glomerular filtration. In prion diseases, abnormal prion proteins are found to accumulate in renal tissues and filtered into urine. Urinary prion protein could serve as a diagnostic biomarker. PrPC plays a role in cellular signaling pathways, reno-protective effects, and kidney iron uptake. PrPC signaling affects mitochondrial function via the ERK pathway and is affected by the regulatory influence of microRNAs, small molecules, and signaling proteins. Targeting PrPC in acute and chronic kidney disease could help improve iron homeostasis, ameliorate damage from ischemia/reperfusion injury, and enhance the efficacy of mesenchymal stem/stromal cell or extracellular vesicle-based therapeutic strategies. PrPC may also be under the influence of BMP/Smad signaling and affect the progression of TGF-β-related renal fibrosis. PrPC conveys TNF-α resistance in some renal cancers, and therefore, the coadministration of anti-PrPC antibodies improves chemotherapy. PrPC can be used to design antibody–drug conjugates, aptamer–drug conjugates, and customized tissue inhibitors of metalloproteinases to suppress cancer. With preclinical studies demonstrating promising results, further research on PrPC in the kidney may lead to innovative PrPC-based therapeutic strategies for renal disease.
6
Das, Alvin S., and Wen-Quan Zou. "Prions: Beyond a Single Protein." Clinical Microbiology Reviews 29, no. 3 (May 25, 2016): 633–58. http://dx.doi.org/10.1128/cmr.00046-15.
Повний текст джерелаАнотація:
SUMMARYSince the term protein was first coined in 1838 and protein was discovered to be the essential component of fibrin and albumin, all cellular proteins were presumed to play beneficial roles in plants and mammals. However, in 1967, Griffith proposed that proteins could be infectious pathogens and postulated their involvement in scrapie, a universally fatal transmissible spongiform encephalopathy in goats and sheep. Nevertheless, this novel hypothesis had not been evidenced until 1982, when Prusiner and coworkers purified infectious particles from scrapie-infected hamster brains and demonstrated that they consisted of a specific protein that he called a “prion.” Unprecedentedly, the infectious prion pathogen is actually derived from its endogenous cellular form in the central nervous system. Unlike other infectious agents, such as bacteria, viruses, and fungi, prions do not contain genetic materials such as DNA or RNA. The unique traits and genetic information of prions are believed to be encoded within the conformational structure and posttranslational modifications of the proteins. Remarkably, prion-like behavior has been recently observed in other cellular proteins—not only in pathogenic roles but also serving physiological functions. The significance of these fascinating developments in prion biology is far beyond the scope of a single cellular protein and its related disease.
7
Dondapati, Divya Teja, Pradeep Reddy Cingaram, Ferhan Ayaydin, Antal Nyeste, Andor Kanyó, Ervin Welker, and Elfrieda Fodor. "Membrane Domain Localization and Interaction of the Prion-Family Proteins, Prion and Shadoo with Calnexin." Membranes 11, no. 12 (December 13, 2021): 978. http://dx.doi.org/10.3390/membranes11120978.
Повний текст джерелаАнотація:
The cellular prion protein (PrPC) is renowned for its infectious conformational isoform PrPSc, capable of templating subsequent conversions of healthy PrPCs and thus triggering the group of incurable diseases known as transmissible spongiform encephalopathies. Besides this mechanism not being fully uncovered, the protein’s physiological role is also elusive. PrPC and its newest, less understood paralog Shadoo are glycosylphosphatidylinositol-anchored proteins highly expressed in the central nervous system. While they share some attributes and neuroprotective actions, opposing roles have also been reported for the two; however, the amount of data about their exact functions is lacking. Protein–protein interactions and membrane microdomain localizations are key determinants of protein function. Accurate identification of these functions for a membrane protein, however, can become biased due to interactions occurring during sample processing. To avoid such artifacts, we apply a non-detergent-based membrane-fractionation approach to study the prion protein and Shadoo. We show that the two proteins occupy similarly raft and non-raft membrane fractions when expressed in N2a cells and that both proteins pull down the chaperone calnexin in both rafts and non-rafts. These indicate their possible binding to calnexin in both types of membrane domains, which might be a necessary requisite to aid the inherently unstable native conformation during their lifetime.
8
Gavín, Rosalina, Laia Lidón, Isidre Ferrer, and José Antonio del Río. "The Quest for Cellular Prion Protein Functions in the Aged and Neurodegenerating Brain." Cells 9, no. 3 (March 2, 2020): 591. http://dx.doi.org/10.3390/cells9030591.
Повний текст джерелаАнотація:
Cellular (also termed ‘natural’) prion protein has been extensively studied for many years for its pathogenic role in prionopathies after misfolding. However, neuroprotective properties of the protein have been demonstrated under various scenarios. In this line, the involvement of the cellular prion protein in neurodegenerative diseases other than prionopathies continues to be widely debated by the scientific community. In fact, studies on knock-out mice show a vast range of physiological functions for the protein that can be supported by its ability as a cell surface scaffold protein. In this review, we first summarize the most commonly described roles of cellular prion protein in neuroprotection, including antioxidant and antiapoptotic activities and modulation of glutamate receptors. Second, in light of recently described interaction between cellular prion protein and some amyloid misfolded proteins, we will also discuss the molecular mechanisms potentially involved in protection against neurodegeneration in pathologies such as Alzheimer’s, Parkinson’s, and Huntington’s diseases.
9
Kovač, Valerija, and Vladka Čurin Šerbec. "Prion Protein: The Molecule of Many Forms and Faces." International Journal of Molecular Sciences 23, no. 3 (January 22, 2022): 1232. http://dx.doi.org/10.3390/ijms23031232.
Повний текст джерелаАнотація:
Cellular prion protein (PrPC) is a glycosylphosphatidylinositol (GPI)-anchored protein most abundantly found in the outer membrane of neurons. Due to structural characteristics (a flexible tail and structured core), PrPC interacts with a wide range of partners. Although PrPC has been proposed to be involved in many physiological functions, only peripheral nerve myelination homeostasis has been confirmed as a bona fide function thus far. PrPC misfolding causes prion diseases and PrPC has been shown to mediate β-rich oligomer-induced neurotoxicity in Alzheimer’s and Parkinson’s disease as well as neuroprotection in ischemia. Upon proteolytic cleavage, PrPC is transformed into released and attached forms of PrP that can, depending on the contained structural characteristics of PrPC, display protective or toxic properties. In this review, we will outline prion protein and prion protein fragment properties as well as overview their involvement with interacting partners and signal pathways in myelination, neuroprotection and neurodegenerative diseases.
10
Lorca, Ramón A., Lorena Varela-Nallar, Nibaldo C. Inestrosa, and J. Pablo Huidobro-Toro. "The Cellular Prion Protein Prevents Copper-Induced Inhibition of P2X4Receptors." International Journal of Alzheimer's Disease 2011 (2011): 1–6. http://dx.doi.org/10.4061/2011/706576.
Повний текст джерелаАнотація:
Although the physiological function of the cellular prion protein (PrPC) remains unknown, several evidences support the notion of its role in copper homeostasis. PrPCbinds Cu2+through a domain composed by four to five repeats of eight amino acids. Previously, we have shown that the perfusion of this domain prevents and reverses the inhibition by Cu2+of the adenosine triphosphate (ATP)-evoked currents in the P2X4receptor subtype, highlighting a modulatory role for PrPCin synaptic transmission through regulation of Cu2+levels. Here, we study the effect of full-length PrPCin Cu2+inhibition of P2X4receptor when both are coexpressed. PrPCexpression does not significantly change the ATP concentration-response curve in oocytes expressing P2X4receptors. However, the presence of PrPCreduces the inhibition by Cu2+of the ATP-elicited currents in these oocytes, confirming our previous observations with the Cu2+binding domain. Thus, our observations suggest a role for PrPCin modulating synaptic activity through binding of extracellular Cu2+.
11
Linden, Rafael, Vilma R. Martins, Marco A. M. Prado, Martín Cammarota, Iván Izquierdo, and Ricardo R. Brentani. "Physiology of the Prion Protein." Physiological Reviews 88, no. 2 (April 2008): 673–728. http://dx.doi.org/10.1152/physrev.00007.2007.
Повний текст джерелаАнотація:
Prion diseases are transmissible spongiform encephalopathies (TSEs), attributed to conformational conversion of the cellular prion protein (PrPC) into an abnormal conformer that accumulates in the brain. Understanding the pathogenesis of TSEs requires the identification of functional properties of PrPC. Here we examine the physiological functions of PrPCat the systemic, cellular, and molecular level. Current data show that both the expression and the engagement of PrPCwith a variety of ligands modulate the following: 1) functions of the nervous and immune systems, including memory and inflammatory reactions; 2) cell proliferation, differentiation, and sensitivity to programmed cell death both in the nervous and immune systems, as well as in various cell lines; 3) the activity of numerous signal transduction pathways, including cAMP/protein kinase A, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt pathways, as well as soluble non-receptor tyrosine kinases; and 4) trafficking of PrPCboth laterally among distinct plasma membrane domains, and along endocytic pathways, on top of continuous, rapid recycling. A unified view of these functional properties indicates that the prion protein is a dynamic cell surface platform for the assembly of signaling modules, based on which selective interactions with many ligands and transmembrane signaling pathways translate into wide-range consequences upon both physiology and behavior.
12
Aguzzi, Adriano, and Anna Maria Calella. "Prions: Protein Aggregation and Infectious Diseases." Physiological Reviews 89, no. 4 (October 2009): 1105–52. http://dx.doi.org/10.1152/physrev.00006.2009.
Повний текст джерелаАнотація:
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.
13
Prado, Mariana Brandão, Maria Isabel Melo Escobar, Rodrigo Nunes Alves, Bárbara Paranhos Coelho, Camila Felix de Lima Fernandes, Jacqueline Marcia Boccacino, Rebeca Piatniczka Iglesia, and Marilene Hohmuth Lopes. "Prion Protein at the Leading Edge: Its Role in Cell Motility." International Journal of Molecular Sciences 21, no. 18 (September 12, 2020): 6677. http://dx.doi.org/10.3390/ijms21186677.
Повний текст джерелаАнотація:
Cell motility is a central process involved in fundamental biological phenomena during embryonic development, wound healing, immune surveillance, and cancer spreading. Cell movement is complex and dynamic and requires the coordinated activity of cytoskeletal, membrane, adhesion and extracellular proteins. Cellular prion protein (PrPC) has been implicated in distinct aspects of cell motility, including axonal growth, transendothelial migration, epithelial–mesenchymal transition, formation of lamellipodia, and tumor migration and invasion. The preferential location of PrPC on cell membrane favors its function as a pivotal molecule in cell motile phenotype, being able to serve as a scaffold protein for extracellular matrix proteins, cell surface receptors, and cytoskeletal multiprotein complexes to modulate their activities in cellular movement. Evidence points to PrPC mediating interactions of multiple key elements of cell motility at the intra- and extracellular levels, such as integrins and matrix proteins, also regulating cell adhesion molecule stability and cell adhesion cytoskeleton dynamics. Understanding the molecular mechanisms that govern cell motility is critical for tissue homeostasis, since uncontrolled cell movement results in pathological conditions such as developmental diseases and tumor dissemination. In this review, we discuss the relevant contribution of PrPC in several aspects of cell motility, unveiling new insights into both PrPC function and mechanism in a multifaceted manner either in physiological or pathological contexts.
14
Caldarulo, Enrico, Alessandro Barducci, Kurt Wüthrich та Michele Parrinello. "Prion protein β2–α2 loop conformational landscape". Proceedings of the National Academy of Sciences 114, № 36 (21 серпня 2017): 9617–22. http://dx.doi.org/10.1073/pnas.1712155114.
Повний текст джерелаАнотація:
In transmissible spongiform encephalopathies (TSEs), which are lethal neurodegenerative diseases that affect humans and a wide range of other mammalian species, the normal “cellular” prion protein (PrPC) is transformed into amyloid aggregates representing the “scrapie form” of the protein (PrPSc). Continued research on this system is of keen interest, since new information on the physiological function of PrPC in healthy organisms is emerging, as well as new data on the mechanism of the transformation of PrPC to PrPSc. In this paper we used two different approaches: a combination of the well-tempered ensemble (WTE) and parallel tempering (PT) schemes and metadynamics (MetaD) to characterize the conformational free-energy surface of PrPC. The focus of the data analysis was on an 11-residue polypeptide segment in mouse PrPC(121–231) that includes the β2–α2 loop of residues 167–170, for which a correlation between structure and susceptibility to prion disease has previously been described. This study includes wild-type mouse PrPC and a variant with the single-residue replacement Y169A. The resulting detailed conformational landscapes complement in an integrative manner the available experimental data on PrPC, providing quantitative insights into the nature of the structural transition-related function of the β2–α2 loop.
15
Loh, Doris, and Russel J. Reiter. "Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance." Molecules 27, no. 3 (January 21, 2022): 705. http://dx.doi.org/10.3390/molecules27030705.
Повний текст джерелаАнотація:
The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.
16
Khosravani, Houman, Yunfeng Zhang, Shigeki Tsutsui, Shahid Hameed, Christophe Altier, Jawed Hamid, Lina Chen, et al. "Prion protein attenuates excitotoxicity by inhibiting NMDA receptors." Journal of Cell Biology 181, no. 3 (April 28, 2008): 551–65. http://dx.doi.org/10.1083/jcb.200711002.
Повний текст джерелаАнотація:
It is well established that misfolded forms of cellular prion protein (PrP [PrPC]) are crucial in the genesis and progression of transmissible spongiform encephalitis, whereas the function of native PrPC remains incompletely understood. To determine the physiological role of PrPC, we examine the neurophysiological properties of hippocampal neurons isolated from PrP-null mice. We show that PrP-null mouse neurons exhibit enhanced and drastically prolonged N-methyl-d-aspartate (NMDA)–evoked currents as a result of a functional upregulation of NMDA receptors (NMDARs) containing NR2D subunits. These effects are phenocopied by RNA interference and are rescued upon the overexpression of exogenous PrPC. The enhanced NMDAR activity results in an increase in neuronal excitability as well as enhanced glutamate excitotoxicity both in vitro and in vivo. Thus, native PrPC mediates an important neuroprotective role by virtue of its ability to inhibit NR2D subunits.
17
Robertson, Catherine, Stephanie A. Booth, Daniel R. Beniac, Michael B. Coulthart, Timothy F. Booth, and Archibald McNicol. "Cellular prion protein is released on exosomes from activated platelets." Blood 107, no. 10 (May 15, 2006): 3907–11. http://dx.doi.org/10.1182/blood-2005-02-0802.
Повний текст джерелаАнотація:
Cellular prion protein (PrPC) is a glycophosphatidylinositol (GPI)–anchored protein, of unknown function, found in a number of tissues throughout the body, including several blood components of which platelets constitute the largest reservoir in humans. It is widely believed that a misfolded, protease-resistant form of PrPC, PrPSc, is responsible for the transmissible spongiform encephalopathy (TSE) group of fatal neurodegenerative diseases. Although the pathogenesis of TSEs is poorly understood, it is known that PrPC must be present in order for the disease to progress; thus, it is important to determine the physiologic function of PrPC. Resolving the location of PrPC in blood will provide valuable clues as to its function. PrPC was previously shown to be on the alpha granule membrane of resting platelets. In the current study platelet activation led to the transient expression of PrPC on the platelet surface and its subsequent release on both microvesicles and exosomes. The presence of PrPC on platelet-derived exosomes suggests a possible mechanism for PrPC transport in blood and for cell-to-cell transmission.
18
Varela-Nallar, Lorena, Enrique M. Toledo, Luis F. Larrondo, Ana L. B. Cabral, Vilma R. Martins, and Nibaldo C. Inestrosa. "Induction of cellular prion protein gene expression by copper in neurons." American Journal of Physiology-Cell Physiology 290, no. 1 (January 2006): C271—C281. http://dx.doi.org/10.1152/ajpcell.00160.2005.
Повний текст джерелаАнотація:
Prion diseases are caused by the conformational transition of the native α-helical cellular prion protein (PrPC) into a β-sheet pathogenic isoform. However, the normal physiological function of PrPC remains elusive. We report herein that copper induces PrPC expression in primary hippocampal and cortical neurons. PrPC induced by copper has a normal glycosylation pattern, is proteinase K-sensitive and reaches the cell surface attached by a glycosyl phosphatidylinositol anchor. Immunofluorescence analysis revealed that copper induces PrPC levels in the cell surface and in an intracellular compartment that we identified as the Golgi complex. In addition, copper induced the activity of a reporter vector driven by the rat PrPC gene ( Prnp) promoter stably transfected into PC12 cells, whereas no effect was observed in glial C6 clones. Also cadmium, but not zinc or manganese, upregulated Prnp promoter activity in PC12 clones. Progressive deletions of the promoter revealed that the region essential for copper modulation contains a putative metal responsive element. Although electrophoretic mobility shift assay demonstrated nuclear protein binding to this element, supershift analysis showed that this is not a binding site for the metal responsive transcription factor-1 (MTF-1). The MTF-1-independent transcriptional activation of Prnp is supported by the lack of Prnp promoter activation by zinc. These findings demonstrate that Prnp expression is upregulated by copper in neuronal cells by an MTF-1-independent mechanism, and suggest a metal-specific modulation of Prnp in neurons.
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Kawahara, Masahiro, Midori Kato-Negishi, and Ken-ichiro Tanaka. "Neurometals in the Pathogenesis of Prion Diseases." International Journal of Molecular Sciences 22, no. 3 (January 28, 2021): 1267. http://dx.doi.org/10.3390/ijms22031267.
Повний текст джерелаАнотація:
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.
20
Martellucci, Stefano, Costantino Santacroce, Francesca Santilli, Valeria Manganelli, Maurizio Sorice, and Vincenzo Mattei. "Prion Protein in Stem Cells: A Lipid Raft Component Involved in the Cellular Differentiation Process." International Journal of Molecular Sciences 21, no. 11 (June 11, 2020): 4168. http://dx.doi.org/10.3390/ijms21114168.
Повний текст джерелаАнотація:
The prion protein (PrP) is an enigmatic molecule with a pleiotropic effect on different cell types; it is localized stably in lipid raft microdomains and it is able to recruit downstream signal transduction pathways by its interaction with various biochemical partners. Since its discovery, this lipid raft component has been involved in several functions, although most of the publications focused on the pathological role of the protein. Recent studies report a key role of cellular prion protein (PrPC) in physiological processes, including cellular differentiation. Indeed, the PrPC, whose expression is modulated according to the cell differentiation degree, appears to be part of the multimolecular signaling pathways of the neuronal differentiation process. In this review, we aim to summarize the main findings that report the link between PrPC and stem cells.
21
Ryskalin, Larisa, Francesca Biagioni, Carla L. Busceti, Maria A. Giambelluca, Luca Morelli, Alessandro Frati, and Francesco Fornai. "The Role of Cellular Prion Protein in Promoting Stemness and Differentiation in Cancer." Cancers 13, no. 2 (January 6, 2021): 170. http://dx.doi.org/10.3390/cancers13020170.
Повний текст джерелаАнотація:
Cellular prion protein (PrPC) is seminal to modulate a variety of baseline cell functions to grant homeostasis. The classic role of such a protein was defined as a chaperone-like molecule being able to rescue cell survival. Nonetheless, PrPC also represents the precursor of the deleterious misfolded variant known as scrapie prion protein (PrPSc). This variant is detrimental in a variety of prion disorders. This multi-faceted role of PrP is greatly increased by recent findings showing how PrPC in its folded conformation may foster tumor progression by acting at multiple levels. The present review focuses on such a cancer-promoting effect. The manuscript analyzes recent findings on the occurrence of PrPC in various cancers and discusses the multiple effects, which sustain cancer progression. Within this frame, the effects of PrPC on stemness and differentiation are discussed. A special emphasis is provided on the spreading of PrPC and the epigenetic effects, which are induced in neighboring cells to activate cancer-related genes. These detrimental effects are further discussed in relation to the aberrancy of its physiological and beneficial role on cell homeostasis. A specific paragraph is dedicated to the role of PrPC beyond its effects in the biology of cancer to represent a potential biomarker in the follow up of patients following surgical resection.
22
Khosravani, Houman, Yunfeng Zhang, Shigeki Tsutsui, Shahid Hameed, Jawed Hamid, Christophe Altier, Frank R. Jirik, and Gerald W. Zamponi. "Modulation of NMDA receptors by prion proteins." Clinical & Investigative Medicine 30, no. 4 (August 1, 2007): 85. http://dx.doi.org/10.25011/cim.v30i4.2859.
Повний текст джерелаАнотація:
Background: The precise physiological function of endogenous cellular prion protein (PrPC) remains unclear. It has been shown that PrP-null mice exhibit reduced LTP and greater susceptability to seizure mortality in several in vivo (e.g. kainic acid) models of epilepsy. In addition, PrP-null mice exhibit greater exctitotoxic cell death in response to kainic acid exposure. Methods: In our study we investigated the synaptic properties of WT and PrP-null mice.
Results: Recordings in the CA1 layer of adult hippocampal slices showed that PrP-null mice exhibit a reduced threshold to evoked responses and no difference in paired-pulse facilitation relative to WT animals. In addition, greater excitability was observed in PrP-null slices in response to zero-Mg2+ induced seizure-like events. Recordings from mature hippocampal cultures showed slightly altered AMPA and GABAA miniature synaptic currents. NMDA mEPSCs were observed to be increased in amplitude and significantly prolonged in decay time. NMDA-evokved currents also exhibited markedly prolonged deactivation kinetics. This effect on evoked NMDA currents was reproduced in WT neurons by PrP-RNAi transfection, and eliminated by PrPC transfection into PrP-null neurons.
Conclusions: These data suggest enhanced NMDA activity in PrP-null neurons. Consistent with this finding, in vitro and in vivo excitotoxicity assays demonstrated increased neuronal cell death in PrP-null cultures and animals upon transient exposure to NMDA. The prolonged deactivation kinetics were most consistent with functional activity/augmentation of NR2D NMDA receptor subunits, and PrP coimmunoprecipiated with NR2D NMDA receptor subunits. This enhanced NMDA receptor function was paralleleld by increased excitotoxicy in Prp-null mice. Our findings demonstrate a novel functional role for PrP as a modulator of synaptic NMDA currents and attributes a neuroprotective function to PrP.
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Benvegnù, Stefano, Paola Roncaglia, Federica Agostini, Cristina Casalone, Cristiano Corona, Stefano Gustincich, and Giuseppe Legname. "Developmental influence of the cellular prion protein on the gene expression profile in mouse hippocampus." Physiological Genomics 43, no. 12 (June 2011): 711–25. http://dx.doi.org/10.1152/physiolgenomics.00205.2010.
Повний текст джерелаАнотація:
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.
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Monette, Anne, and Andrew J. Mouland. "Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates." Viruses 12, no. 10 (October 18, 2020): 1179. http://dx.doi.org/10.3390/v12101179.
Повний текст джерелаАнотація:
Liquid-liquid phase separation (LLPS) is a rapidly growing research focus due to numerous demonstrations that many cellular proteins phase-separate to form biomolecular condensates (BMCs) that nucleate membraneless organelles (MLOs). A growing repertoire of mechanisms supporting BMC formation, composition, dynamics, and functions are becoming elucidated. BMCs are now appreciated as required for several steps of gene regulation, while their deregulation promotes pathological aggregates, such as stress granules (SGs) and insoluble irreversible plaques that are hallmarks of neurodegenerative diseases. Treatment of BMC-related diseases will greatly benefit from identification of therapeutics preventing pathological aggregates while sparing BMCs required for cellular functions. Numerous viruses that block SG assembly also utilize or engineer BMCs for their replication. While BMC formation first depends on prion-like disordered protein domains (PrLDs), metal ion-controlled RNA-binding domains (RBDs) also orchestrate their formation. Virus replication and viral genomic RNA (vRNA) packaging dynamics involving nucleocapsid (NC) proteins and their orthologs rely on Zinc (Zn) availability, while virus morphology and infectivity are negatively influenced by excess Copper (Cu). While virus infections modify physiological metal homeostasis towards an increased copper to zinc ratio (Cu/Zn), how and why they do this remains elusive. Following our recent finding that pan-retroviruses employ Zn for NC-mediated LLPS for virus assembly, we present a pan-virus bioinformatics and literature meta-analysis study identifying metal-based mechanisms linking virus-induced BMCs to neurodegenerative disease processes. We discover that conserved degree and placement of PrLDs juxtaposing metal-regulated RBDs are associated with disease-causing prion-like proteins and are common features of viral proteins responsible for virus capsid assembly and structure. Virus infections both modulate gene expression of metalloproteins and interfere with metal homeostasis, representing an additional virus strategy impeding physiological and cellular antiviral responses. Our analyses reveal that metal-coordinated virus NC protein PrLDs initiate LLPS that nucleate pan-virus assembly and contribute to their persistence as cell-free infectious aerosol droplets. Virus aerosol droplets and insoluble neurological disease aggregates should be eliminated by physiological or environmental metals that outcompete PrLD-bound metals. While environmental metals can control virus spreading via aerosol droplets, therapeutic interference with metals or metalloproteins represent additional attractive avenues against pan-virus infection and virus-exacerbated neurological diseases.
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D’Alessio, Stefania, Stefanía Thorgeirsdóttir, Igor Kraev, Karl Skírnisson, and Sigrun Lange. "Post-Translational Protein Deimination Signatures in Plasma and Plasma EVs of Reindeer (Rangifer tarandus)." Biology 10, no. 3 (March 13, 2021): 222. http://dx.doi.org/10.3390/biology10030222.
Повний текст джерелаАнотація:
The reindeer (caribou) Rangifer tarandus is a Cervidae in the order Artiodactyla. Reindeer are sedentary and migratory populations with circumpolar distribution in the Arctic, Northern Europe, Siberia and North America. Reindeer are an important wild and domesticated species, and have developed various adaptive strategies to extreme environments. Importantly, deer have also been identified to be putative zoonotic carriers, including for parasites, prions and coronavirus. Therefore, novel insights into immune-related markers are of considerable interest. Peptidylarginine deiminases (PADs) are a phylogenetically conserved enzyme family which causes post-translational protein deimination by converting arginine into citrulline in target proteins. This affects protein function in health and disease. Extracellular vesicles (EVs) participate in cellular communication, in physiological and pathological processes, via transfer of cargo material, and their release is partly regulated by PADs. This study assessed deiminated protein and EV profile signatures in plasma from sixteen healthy wild female reindeer, collected in Iceland during screening for parasites and chronic wasting disease. Reindeer plasma EV profiles showed a poly-dispersed distribution from 30 to 400 nm and were positive for phylogenetically conserved EV-specific markers. Deiminated proteins were isolated from whole plasma and plasma EVs, identified by proteomic analysis and protein interaction networks assessed by KEGG and GO analysis. This revealed a large number of deimination-enriched pathways for immunity and metabolism, with some differences between whole plasma and EVs. While shared KEGG pathways for whole plasma and plasma EVs included complement and coagulation pathways, KEGG pathways specific for EVs were for protein digestion and absorption, platelet activation, amoebiasis, the AGE–RAGE signaling pathway in diabetic complications, ECM receptor interaction, the relaxin signaling pathway and the estrogen signaling pathway. KEGG pathways specific for whole plasma were pertussis, ferroptosis, SLE, thyroid hormone synthesis, phagosome, Staphylococcus aureus infection, vitamin digestion and absorption, and prion disease. Further differences were also found between molecular function and biological processes GO pathways when comparing functional STRING networks for deiminated proteins in EVs, compared with deiminated proteins in whole plasma. This study highlights deiminated proteins and EVs as candidate biomarkers for reindeer health and may provide information on regulation of immune pathways in physiological and pathological processes, including neurodegenerative (prion) disease and zoonosis.
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Khosravani, H., Y. Zhang, S. Tsutsui, S. Hameed, C. Altier, J. Hamid, L. Chen, et al. "LACK OF CELLULAR PRION PROTEIN UNMASKS NMDA NR2D SUBUNIT RECEPTOR FUNCTION WITH CONSEQUENCES TOWARD SYNAPTIC TRANSMISSION AND EXCITOTOXICITY." Clinical & Investigative Medicine 31, no. 4 (August 1, 2008): 14. http://dx.doi.org/10.25011/cim.v31i4.4811.
Повний текст джерелаАнотація:
Background: The physiological functions of endogenous cellular prion protein (PrPC)is incompletely understood. Previously, it has been shown that PrP-null mice exhibit reduced long-term (synaptic) potentiation and greater susceptibility to seizure mortality in several in vivo models of epilepsy. In addition, PrP-null neurons in culture exhibit greater excito toxic cell death in response to kainic acid exposure, and in several models of oxidative stress. Although PrP seems toplay a protective role against various forms of cellular insults, the precise mechanism of such action is unknown. Methods: We investigated the synaptic properties of WT and PrP-null mice using cultured neurons and also brain slices from adult mice. Synaptic activity was assessed using whole-cell voltage clamp. We recorded spontaneous and evoked synaptic potentials. Extracellular field recordings of brain slices were also performed. Pharmacological agents were used to isolate all components of glutamatergic and GABA(A) mediated synaptic transmission. In addition, weassessed the effect of NMDA excitotoxicity in WT and PrP-null neurons using in vitro and in vivo experiments. We also used immunostaining, coimmunoprecipitation, and protein expression studies to quantify the relation between NMDA subtype expression and localization relative to native PrP. Results: Recordings in the CA1 layer of adult hippocampal slices showed thatPrP-null mice exhibit a reduced threshold to evoked responses, exhibited basal hyperexcitability, and in a model of zero-Mg2+ seizures also showed lower seizure threshold. No differences were observed in paired-pulse facilitation relative to WT animals. Recordings from mature hippocampal cultures showed slightly altered AMPA and GABAA miniature synaptic currents. NMDA mEPSCs were observed to be increased in amplitude and significantly prolonged in decaytime. NMDA-evoked currents also exhibited markedly prolonged deactivation kinetics. This effect on evoked NMDA currents was reproduced in WT neurons byindependent PrP-RNAi, NR2D-RNAi transfection, and eliminated by PrPCtransfection into PrP-null neurons. In addition, PrP coimmunoprecipitated with NR2D and not NR2B NMDA receptor subunits. In vitro and in vivo experiments utilizing transient exposure to NMDA showed greater cell death in PrP-nullneurons, which was significantly reduced by application of an NMDA receptor antagonist. Conclusions: These data suggest that enhanced NMDA activity is present in PrP-null neurons. Consistent with this finding, in vitro and in vivo excitotoxicity assays demonstrated increased neuronal cell death in PrP-null cultures and animals upon transient exposure to NMDA. This was confirmed at the level of synaptic currents showing prolonged receptor deactivation kinetics that were most consistent with functional activation of NR2D NMDA receptor subunits. Enhanced NMDA receptor function was paralleled by increased excitotoxicity in PrP-null mice. Our findings demonstrate a novel functional role for PrP as a modulator of synaptic NMDA currents and attributes a neuroprotective function to PrP.
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Glierova, Hana, Martin Panigaj, Jana Semberova, Olga Janouskova, Eva Dvorakova, Jan Zivny, and Karel Holada. "Impairment of Erythropoiesis In Inbred Cellular Prion Protein Deficient Mice." Blood 116, no. 21 (November 19, 2010): 2032. http://dx.doi.org/10.1182/blood.v116.21.2032.2032.
Повний текст джерелаАнотація:
Abstract Abstract 2032 Cellular prion protein (PrPc) plays a key role in pathogenesis of prion diseases, however, its physiologic function remains unclear. The involvement of PrPc in hematopoiesis was suggested by importance of its expression for self renewal and survival of long term repopulating hematopoietic stem cells. Prion diseases were shown to deregulate transcription of several erythroid genes and we have demonstrated reduction of erythroid cell and erythropoietin production in FVB PrP-/- (Zurich I) mice in response to acute anemia (Zivny J. et al. Blood Cells Mol Dis. 2008;40:302-307). In this study, we exploited different mouse models with manipulated level of PrPc expression to verify the role of PrPc in erythropoiesis. First set of experiments was carried out on PrP-/- (Zurich I) and Tga20 PrP over-expressing mice on a mixed C57Bl6/129Sv genetic background. Inbred C57Bl6 mice served as a wild type control (WT). Induction of acute anemia by phenylhydrazine (PHZ) in PrP-/- and WT mice (n=18) led to drop in the hematocrit (HCT) from 52.5±1.5 and 49.8±2.5% to 37.9± 1.0 and 41.9±3.0% after 24 h, respectively. The course of anemia was significantly deeper in PrP-/- mice at 72 h, 96 h and 120 h (p < 0.01) after PHZ administration. Plasma levels of erythropoietin (Epo) in response to anemia reached higher maximum levels in PrP-/- than WT mice (2250 vs. 1810 pg/mL) although rose more slowly. The level of Epo mRNA in kidneys increased approximately 30-fold in both, WT and PrP-/- mice, however, in WT mice peaked at 24 h whereas in KO mice at 96 h. We repeated the study with smaller groups of PrP-/- and Tga20 mice (n=9) and analysed samples 24 h and 96 h post anemia induction. Random PrP gene re-introduction in Tga20 mice rescued the animals from severe anemia. Decrease in HCT after PHZ administration was significantly lower in Tga20 comparing to PrP-/- mice and was accompanied by less elevated reticulocyte (RTC) count, plasma Epo level and level of Epo mRNA in kidneys. Next we studied the dynamics of unchallenged erythropoiesis in PrP-/-, Tga20 and WT mice by in vivo labelling of blood cells with NHS-biotin and subsequent flow cytometric analysis of relative numbers of newly produced non-labelled RBC. WT mice had significantly enhanced turnover of RBC with higher counts of non-labelled RBC comparing to PrP-/- during 46 days of chase (p < 0.05). Half- life of labeled RBC in WT mice was 20 days, but 32 and 30 days in PrP-/- and Tga20 mice, respectively. Tga20 mice displayed tendency to increased RBC turnover over PrP-/- mice, but the difference was significant only 2 and 33 days after initiation of the experiment. Having in mind possible limitations of experiments conducted in genetically modified inbred mice we have designed second set of experiments in more stringent animal models. We mated C57Bl6/129Sv PrP-/- mice with inbred C57Bl6 and outbred CD-1 mice. Heterozygotes in F1 generation were mated and their PrP -/-, PrP -/+ and PrP +/+ offspring used in the experiments. Anemia was induced by PHZ and blood was sampled from tail vein at defined time points and HCT and RTC count were analysed. In C57Bl6 crossbreeds we observed significantly higher starting HCT level in PrP-/- mice (p < 0.05) compared to PrP-/+ and PrP+/+ mice reaching 53.2±2.3, 50.0±2.1 and 49±2.9%, respectively. Similar decrease in HCT was observed for all PrP groups 24 h after PHZ administration, however, significant differences between PrP-/- and PrP+/+ mice were recorded at 48 h and 72 h. The recovery to normal HCT was again retarded in PrP-/- mice. RTC counts rose more rapidly in PrP+/+ mice after PHZ administration and declined to basal levels faster than in PrP-/- mice, the difference reached significance at 24 h, 48 h and 96 h. Dynamics of unchallenged erythropoiesis in C57Bl6 crossbreeds was similar in all three PrP genotypes with no significant differences in numbers of newly produced RBC during 57 days of the experiment. In CD-1 crossbreed mice no significant differences in HCT and RTC counts were detected after PHZ induced anemia among PrP-/-, PrP-/+ and PrP+/+ siblings. Also the dynamics of unchallenged erythropoiesis was similar in all PrP genotypes. To sum up, our data confirmed the role of PrPc in stress erythropoiesis in studied inbred mouse models. In outbred model the effect of PrP deletion on erythropoiesis seems to be compensated. (GACR310/08/0878, GAUK86408) Disclosures: No relevant conflicts of interest to declare.
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Noori, Leila, Kamila Filip, Zohreh Nazmara, Simin Mahakizadeh, Gholamreza Hassanzadeh, Celeste Caruso Caruso Bavisotto, Fabio Bucchieri, et al. "Contribution of Extracellular Vesicles and Molecular Chaperones in Age-Related Neurodegenerative Disorders of the CNS." International Journal of Molecular Sciences 24, no. 2 (January 4, 2023): 927. http://dx.doi.org/10.3390/ijms24020927.
Повний текст джерелаАнотація:
Many neurodegenerative disorders are characterized by the abnormal aggregation of misfolded proteins that form amyloid deposits which possess prion-like behavior such as self-replication, intercellular transmission, and consequent induction of native forms of the same protein in surrounding cells. The distribution of the accumulated proteins and their correlated toxicity seem to be involved in the progression of nervous system degeneration. Molecular chaperones are known to maintain proteostasis, contribute to protein refolding to protect their function, and eliminate fatally misfolded proteins, prohibiting harmful effects. However, chaperone network efficiency declines during aging, prompting the onset and the development of neurological disorders. Extracellular vesicles (EVs) are tiny membranous structures produced by a wide range of cells under physiological and pathological conditions, suggesting their significant role in fundamental processes particularly in cellular communication. They modulate the behavior of nearby and distant cells through their biological cargo. In the pathological context, EVs transport disease-causing entities, including prions, α-syn, and tau, helping to spread damage to non-affected areas and accelerating the progression of neurodegeneration. However, EVs are considered effective for delivering therapeutic factors to the nervous system, since they are capable of crossing the blood–brain barrier (BBB) and are involved in the transportation of a variety of cellular entities. Here, we review the neurodegeneration process caused mainly by the inefficiency of chaperone systems as well as EV performance in neuropathies, their potential as diagnostic biomarkers and a promising EV-based therapeutic approach.
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Tamaki, Yoshitaka, and Makoto Urushitani. "Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD." International Journal of Molecular Sciences 23, no. 20 (October 19, 2022): 12508. http://dx.doi.org/10.3390/ijms232012508.
Повний текст джерелаАнотація:
TAR DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in pivotal cellular functions, especially in RNA metabolism. Hyperphosphorylated and ubiquitinated TDP-43-positive neuronal cytoplasmic inclusions are identified in the brain and spinal cord in most cases of amyotrophic lateral sclerosis (ALS) and a substantial proportion of frontotemporal lobar degeneration (FTLD) cases. TDP-43 dysfunctions and cytoplasmic aggregation seem to be the central pathogenicity in ALS and FTLD. Therefore, unraveling both the physiological and pathological mechanisms of TDP-43 may enable the exploration of novel therapeutic strategies. This review highlights the current understanding of TDP-43 biology and pathology, describing the cellular processes involved in the pathogeneses of ALS and FTLD, such as post-translational modifications, RNA metabolism, liquid–liquid phase separation, proteolysis, and the potential prion-like propagation propensity of the TDP-43 inclusions.
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Holada, Karel, Jan Simak, and Jaroslav G. Vostal. "The Post-Transfusion Recovery and Survival of Red Blood Cells in Mice Is Affected by the Expression of Cellular Prion Protein." Blood 108, no. 11 (November 16, 2006): 959. http://dx.doi.org/10.1182/blood.v108.11.959.959.
Повний текст джерелаАнотація:
Abstract Three documented transfusion cases of vCJD underline the need of better insight in blood prion protein biology. Cellular prion protein (PrPc) plays key role in the pathophysiology of prion diseases. Its expression by cells is necessary for amplification of infectious prions and the disease process itself. Physiological function of PrPc remains obscure. Its clarification may provide important clues for the development of urgently needed blood test and effective disease treatment. PrPc is expressed on CD34+ hematopoietic stem cells and its expression is regulated during blood cell differentiation. Recently the importance of PrPc for self-renewal of long-term repopulating hematopoietic stem cells was suggested and other studies reported the protective function of PrPc against oxidative stress and apoptosis in various cell cultures. We previously demonstrated that human as well as mouse red blood cells (RBC) express approximately 200 PrPc molecules / cell (Holada et al., BJH 2000, 110, 472–80). To test if the PrPc expression plays a role in the post-transfusion recovery and survival of RBC we carried out transfusion study in mice. RBC isolated from blood of wild type (WT) and PrP knockout (KO) FVB mice were labeled “in vitro” by different levels of NHS-biotin. The labeling was optimized to allow simultaneous detection of both populations of RBC in mouse blood using flow cytometry. To exclude the influence of different level of cell biotinylation on the experiment outcome two mixtures of RBC were prepared. The first contained KO RBC labeled with high and WT RBC with low level of biotin and the second mixture contained cells labeled “vice versa”. Each mixture was injected via tail vein in a group of WT mice (n=5) and the survival of RBCs was followed. Samples were analyzed on day 1, 2, 3, 6, 9, 15, 21 and 29. The count of biotinylated RBC was measured in comparison to 100 000 nonlabeled recipient RBC. Simultaneously the expression of PrPc on RBC was monitored using flow cytometry with MAb 6H4. KO RBC displayed significantly higher first day post-transfusion recovery compared to WT RBC in both groups of mice (81 ± 3 % vs. 74 ± 3 %, P<0.005 and 90 ± 4 % vs. 80 ± 4 %, P<0.005). The slope of the RBC survival curve in all individual mice during the initial 15 days was steeper for KO RBC (mavg = − 3.44) than for WT RBC (mavg = − 2.37) suggesting the protective role of PrPc in circulating RBC. The difference in the slope diminished during the 15 to 29 day period which was accompanied by a 50% decrease of PrPc surface expression on transfused WT RBC. To confirm our data the identical experiment was carried out in a group of KO mice (n=5) transfused with a mixture containing KO RBC labeled with low and WT RBC with high level of biotin. Again the first day post-transfusion recovery was higher for KO RBC (80 ± 6 % vs. 75 ± 6 %, P<0.05) and the initial slope of the KO RBC survival curve was steeper in all mice in the group. Our data suggest that PrPc expression plays role in the post-transfusion recovery and survival of RBC. The observation that WT RBC disappear from the circulation at lower rate than KO RBC until their level of surface PrPc reaches 50% is compatible with the protective role of PrPc expression on cells. Taken together our study demonstrates that physiological role of PrPc expression on RBC may lay in facilitating their longer survival in circulation. (GACR 310/04/0419, MSMT 0021620806).
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Carlston, Colleen, Robin Weinmann, Natalia Stec, Simona Abbatemarco, Francoise Schwager, Jing Wang, Huiwu Ouyang, Collin Y. Ewald, Monica Gotta, and Christopher M. Hammell. "PQN-59 antagonizes microRNA-mediated repression during post-embryonic temporal patterning and modulates translation and stress granule formation in C. elegans." PLOS Genetics 17, no. 11 (November 22, 2021): e1009599. http://dx.doi.org/10.1371/journal.pgen.1009599.
Повний текст джерелаАнотація:
microRNAs (miRNAs) are potent regulators of gene expression that function in a variety of developmental and physiological processes by dampening the expression of their target genes at a post-transcriptional level. In many gene regulatory networks (GRNs), miRNAs function in a switch-like manner whereby their expression and activity elicit a transition from one stable pattern of gene expression to a distinct, equally stable pattern required to define a nascent cell fate. While the importance of miRNAs that function in this capacity are clear, we have less of an understanding of the cellular factors and mechanisms that ensure the robustness of this form of regulatory bistability. In a screen to identify suppressors of temporal patterning phenotypes that result from ineffective miRNA-mediated target repression, we identified pqn-59, an ortholog of human UBAP2L, as a novel factor that antagonizes the activities of multiple heterochronic miRNAs. Specifically, we find that depletion of pqn-59 can restore normal development in animals with reduced lin-4 and let-7-family miRNA activity. Importantly, inactivation of pqn-59 is not sufficient to bypass the requirement of these regulatory RNAs within the heterochronic GRN. The pqn-59 gene encodes an abundant, cytoplasmically-localized, unstructured protein that harbors three essential “prion-like” domains. These domains exhibit LLPS properties in vitro and normally function to limit PQN-59 diffusion in the cytoplasm in vivo. Like human UBAP2L, PQN-59’s localization becomes highly dynamic during stress conditions where it re-distributes to cytoplasmic stress granules and is important for their formation. Proteomic analysis of PQN-59 complexes from embryonic extracts indicates that PQN-59 and human UBAP2L interact with orthologous cellular components involved in RNA metabolism and promoting protein translation and that PQN-59 additionally interacts with proteins involved in transcription and intracellular transport. Finally, we demonstrate that pqn-59 depletion reduces protein translation and also results in the stabilization of several mature miRNAs (including those involved in temporal patterning). These data suggest that PQN-59 may ensure the bistability of some GRNs that require miRNA functions by promoting miRNA turnover and, like UBAP2L, enhancing protein translation.
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Nuvolone, Mario, Mario Hermann, Silvia Sorce, Giancarlo Russo, Cinzia Tiberi, Petra Schwarz, Eric Minikel, Despina Sanoudou, Pawel Pelczar, and Adriano Aguzzi. "Strictly co-isogenic C57BL/6J-Prnp−/− mice: A rigorous resource for prion science." Journal of Experimental Medicine 213, no. 3 (February 29, 2016): 313–27. http://dx.doi.org/10.1084/jem.20151610.
Повний текст джерелаАнотація:
Although its involvement in prion replication and neurotoxicity during transmissible spongiform encephalopathies is undisputed, the physiological role of the cellular prion protein (PrPC) remains enigmatic. A plethora of functions have been ascribed to PrPC based on phenotypes of Prnp−/− mice. However, all currently available Prnp−/− lines were generated in embryonic stem cells from the 129 strain of the laboratory mouse and mostly crossed to non-129 strains. Therefore, Prnp-linked loci polymorphic between 129 and the backcrossing strain resulted in systematic genetic confounders and led to erroneous conclusions. We used TALEN-mediated genome editing in fertilized mouse oocytes to create the Zurich-3 (ZH3) Prnp-ablated allele on a pure C57BL/6J genetic background. Genomic, transcriptional, and phenotypic characterization of PrnpZH3/ZH3 mice failed to identify phenotypes previously described in non–co-isogenic Prnp−/− mice. However, aged PrnpZH3/ZH3 mice developed a chronic demyelinating peripheral neuropathy, confirming the crucial involvement of PrPC in peripheral myelin maintenance. This new line represents a rigorous genetic resource for studying the role of PrPC in physiology and disease.
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Messerli, Mark A., and Anyesha Sarkar. "Advances in Electrochemistry for Monitoring Cellular Chemical Flux." Current Medicinal Chemistry 26, no. 26 (October 22, 2019): 4984–5002. http://dx.doi.org/10.2174/0929867326666190506111629.
Повний текст джерелаАнотація:
The transport of molecules and inorganic ions across the plasma membrane results in chemical fluxes that reflect cellular function in healthy and diseased states. Measurement of these chemical fluxes enables the characterization of protein function and transporter stoichiometry, characterization of the viability of single cells and embryos prior to implantation, and screening of pharmaceutical agents. Electrochemical sensors are sensitive and noninvasive tools for measuring chemical fluxes immediately outside the cells in the boundary layer, that are capable of monitoring a diverse range of transported analytes including inorganic ions, gases, neurotransmitters, hormones, and pharmaceutical agents. Used on their own or in combination with other methods, these sensors continue to expand our understanding of the function of rare cells and small tissues. Advances in sensor construction and detection strategies continue to improve sensitivity under physiological conditions, diversify analyte detection, and increase throughput. These advances will be discussed in the context of addressing technical challenges to measuring in the boundary layer of cells and measuring the resultant changes to the chemical concentration in the bulk media.
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Puig, Berta, Denise Yang, Santra Brenna, Hermann Clemens Altmeppen, and Tim Magnus. "Show Me Your Friends and I Tell You Who You Are: The Many Facets of Prion Protein in Stroke." Cells 9, no. 7 (July 2, 2020): 1609. http://dx.doi.org/10.3390/cells9071609.
Повний текст джерелаАнотація:
Ischemic stroke belongs to the leading causes of mortality and disability worldwide. Although treatments for the acute phase of stroke are available, not all patients are eligible. There is a need to search for therapeutic options to promote neurological recovery after stroke. The cellular prion protein (PrPC) has been consistently linked to a neuroprotective role after ischemic damage: it is upregulated in the penumbra area following stroke in humans, and animal models of stroke have shown that lack of PrPC aggravates the ischemic damage and lessens the functional outcome. Mechanistically, these effects can be linked to numerous functions attributed to PrPC: (1) as a signaling partner of the PI3K/Akt and MAPK pathways, (2) as a regulator of glutamate receptors, and (3) promoting stem cell homing mechanisms, leading to angio- and neurogenesis. PrPC can be cleaved at different sites and the proteolytic fragments can account for the manifold functions. Moreover, PrPC is present on extracellular vesicles (EVs), released membrane particles originating from all types of cells that have drawn attention as potential therapeutic tools in stroke and many other diseases. Thus, identification of the many mechanisms underlying PrPC-induced neuroprotection will not only provide further understanding of the physiological functions of PrPC but also new ideas for possible treatment options after ischemic stroke.
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Minasov, George, Nicole L. Inniss, Ludmilla Shuvalova, Wayne F. Anderson, and Karla J. F. Satchell. "Structure of the Monkeypox virus profilin-like protein A42R reveals potential functional differences from cellular profilins." Acta Crystallographica Section F Structural Biology Communications 78, no. 10 (September 26, 2022): 371–77. http://dx.doi.org/10.1107/s2053230x22009128.
Повний текст джерелаАнотація:
The infectious disease human monkeypox is spreading rapidly in 2022, causing a global health crisis. The genomics of Monkeypox virus (MPXV) have been extensively analyzed and reported, although little is known about the virus-encoded proteome. In particular, there are no reported experimental MPXV protein structures other than computational models. Here, a 1.52 Å resolution X-ray structure of the MPXV protein A42R, the first MPXV-encoded protein with a known structure, is reported. A42R shows structural similarity to profilins, which are cellular proteins that are known to function in the regulation of actin cytoskeletal assembly. However, structural comparison of A42R with known members of the profilin family reveals critical differences that support prior biochemical findings that A42R only weakly binds actin and does not bind poly(L-proline). In addition, the analysis suggests that A42R may make distinct interactions with phosphatidylinositol lipids. Overall, the data suggest that the role of A42R in the replication of orthopoxviruses may not be readily determined by comparison to cellular profilins. Furthermore, these findings support the need for increased efforts to determine high-resolution structures of other MPXV proteins to inform physiological studies of the poxvirus infection cycle and to reveal potential new strategies to combat human monkeypox should this emerging infectious disease with pandemic potential become more common in the future.
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Carulla, Patricia, Ana Bribián, Alejandra Rangel, Rosalina Gavín, Isidro Ferrer, Carme Caelles, José Antonio del Río, and Franc Llorens. "Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7–PSD-95 binding." Molecular Biology of the Cell 22, no. 17 (September 2011): 3041–54. http://dx.doi.org/10.1091/mbc.e11-04-0321.
Повний текст джерелаАнотація:
Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol–anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrPSC) induces transmissible spongiform encephalopathies. In contrast, PrPC has a number of physiological functions in several neural processes. Several lines of evidence implicate PrPC in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrPC has been implicated in the inhibition of N-methyl-d-aspartic acid (NMDA)–mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnpo/oJnk3o/o mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrPC-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrPC with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6–PSD-95 interaction after KA injections was favored by the absence of PrPC. Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrPC against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.
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Lidón, Laia, Laura Llaó-Hierro, Mario Nuvolone, Adriano Aguzzi, Jesús Ávila, Isidro Ferrer, José Antonio del Río та Rosalina Gavín. "Tau Exon 10 Inclusion by PrPC through Downregulating GSK3β Activity". International Journal of Molecular Sciences 22, № 10 (20 травня 2021): 5370. http://dx.doi.org/10.3390/ijms22105370.
Повний текст джерелаАнотація:
Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3β, whose activity is inhibited by the cellular prion protein (PrPC), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrPC and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrPC and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrPC ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrPC expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrPC levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3β activity downstream from PrPC in this phenomenon. Our results indicate that PrPC plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3β.
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de Rooij, Laura Adriana, Dirk Jan Mastebroek, Nicky ten Voorde, Elsken van der Wall, Paul Joannes van Diest, and Cathy Beatrice Moelans. "The microRNA Lifecycle in Health and Cancer." Cancers 14, no. 23 (November 23, 2022): 5748. http://dx.doi.org/10.3390/cancers14235748.
Повний текст джерелаАнотація:
MicroRNAs (miRNAs) are small non-coding RNAs of ~22 nucleotides that regulate gene expression at the post-transcriptional level. They can bind to around 60% of all protein-coding genes with an average of 200 targets per miRNA, indicating their important function within physiological and pathological cellular processes. miRNAs can be quickly produced in high amounts through canonical and non-canonical pathways that involve a multitude of steps and proteins. In cancer, miRNA biogenesis, availability and regulation of target expression can be altered to promote tumour progression. This can be due to genetic causes, such as single nucleotide polymorphisms, epigenetic changes, differences in host gene expression, or chromosomal remodelling. Alternatively, post-transcriptional changes in miRNA stability, and defective or absent components and mediators of the miRNA-induced silencing complex can lead to altered miRNA function. This review provides an overview of the current knowledge on the lifecycle of miRNAs in health and cancer. Understanding miRNA function and regulation is fundamental prior to potential future application of miRNAs as cancer biomarkers.
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Lee, Simon C., Christine A. Robson-Doucette, and Michael B. Wheeler. "Uncoupling protein 2 regulates reactive oxygen species formation in islets and influences susceptibility to diabetogenic action of streptozotocin." Journal of Endocrinology 203, no. 1 (July 27, 2009): 33–43. http://dx.doi.org/10.1677/joe-09-0117.
Повний текст джерелаАнотація:
Currently, the physiological function of uncoupling protein-2 (UCP2) in pancreatic islets and its role in the development of diabetes is a matter of great debate. To further investigate the impact of UCP2 on diabetes development, we used streptozotocin (STZ) to experimentally generate diabetes in both wild-type (WT) and UCP2-knockout (UCP2KO) mice. While multiple low-dose STZ injections led to hyperglycemia development over a 14-day period in both WT and UCP2KO mice, we found the development of hyperglycemia to be significantly less severe in the UCP2KO mice. Measurement of insulin and glucagon secretion (in vitro), as well as their plasma concentrations (in vivo), indicated that UCP2-deficiency showed enhanced insulin secretion but impaired α-cell function. Glucagon secretion was attenuated, despite reduced insulin secretion after exposure to STZ, which together contributed to less severe hyperglycemia development in UCP2KO mice. Further experimentation revealed that UCP2-deficient α- and β-cells had chronically higher cellular reactive oxygen species (ROS) levels than the WT prior to STZ application, which correlated with increased basal β- and α-cell mass. Overall, we suggest that increased chronic ROS signaling as a result of UCP2-deficiency contributes to enhanced β-cell function and impairment of α-cell function, leading to an attenuation of STZ-induced hyperglycemia development.
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Fries, Erik, and Aneta Kaczmarczyk. "Inter-alpha-inhibitor, hyaluronan and inflammation." Acta Biochimica Polonica 50, no. 3 (September 30, 2003): 735–42. http://dx.doi.org/10.18388/abp.2003_3664.
Повний текст джерелаАнотація:
Inter-alpha-inhibitor is an abundant plasma protein whose physiological function is only now beginning to be revealed. It consists of three polypeptides: two heavy chains and one light chain called bikunin. Bikunin, which has antiproteolytic activity, carries a chondroitin sulphate chain to which the heavy chains are covalently linked. The heavy chains can be transferred from inter-alpha-inhibitor to hyaluronan molecules and become covalently linked. This reaction seems to be mediated by TSG-6, a protein secreted by various cells upon stimulation by inflammatory cytokines. Inter-alpha-inhibitor has been shown to be required for the stabilization of the cumulus cell-oocyte complex during the expansion that occurs prior to ovulation. Hyaluronan-linked heavy chains in the extracellular matrix of this cellular complex have recently been shown to be tightly bound to TSG-6. Since TSG-6 binds to hyaluronan, its complex with heavy chains could stabilize the extracellular matrix by cross-linking hyaluronan molecules. Heavy chains linked to hyaluronan molecules have also been found in inflamed tissues. The physiological role of these complexes is not known but there are indications that they might protect hyaluronan against fragmentation by reactive oxygen species. TSG-6 also binds to bikunin thereby enhancing its antiplasmin activity. Taken together, these results suggest that inter-alpha-inhibitor is an anti-inflammatory agent which is activated by TSG-6.
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Peña Ccoa, Willmor J., and Glen M. Hocky. "Assessing models of force-dependent unbinding rates via infrequent metadynamics." Journal of Chemical Physics 156, no. 12 (March 28, 2022): 125102. http://dx.doi.org/10.1063/5.0081078.
Повний текст джерелаАнотація:
Protein–ligand interactions are crucial for a wide range of physiological processes. Many cellular functions result in these non-covalent “bonds” being mechanically strained, and this can be integral to proper cellular function. Broadly, two classes of force dependence have been observed—slip bonds, where the unbinding rate increases, and catch bonds, where the unbinding rate decreases. Despite much theoretical work, we cannot predict for which protein–ligand pairs, pulling coordinates, and forces a particular rate dependence will appear. Here, we assess the ability of MD simulations combined with enhanced sampling techniques to probe the force dependence of unbinding rates. We show that the infrequent metadynamics technique correctly produces both catch and slip bonding kinetics for model potentials. We then apply it to the well-studied case of a buckyball in a hydrophobic cavity, which appears to exhibit an ideal slip bond. Finally, we compute the force-dependent unbinding rate of biotin–streptavidin. Here, the complex nature of the unbinding process causes the infrequent metadynamics method to begin to break down due to the presence of unbinding intermediates, despite the use of a previously optimized sampling coordinate. Allowing for this limitation, a combination of kinetic and free energy computations predicts an overall slip bond for larger forces consistent with prior experimental results although there are substantial deviations at small forces that require further investigation. This work demonstrates the promise of predicting force-dependent unbinding rates using enhanced sampling MD techniques while also revealing the methodological barriers that must be overcome to tackle more complex targets in the future.
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Griffoni, Cristiana, Mattia Toni, Enzo Spisni, Maria Cristina Bianco, Spartaco Santi, Massimo Riccio, and Vittorio Tomasi. "The Cellular Prion Protein: Biochemistry, Topology, and Physiologic Functions." Cell Biochemistry and Biophysics 38, no. 3 (2003): 287–304. http://dx.doi.org/10.1385/cbb:38:3:287.
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Prcina, Michal, and Eva Kontsekova. "Has prion protein important physiological function?" Medical Hypotheses 76, no. 4 (April 2011): 567–69. http://dx.doi.org/10.1016/j.mehy.2011.01.002.
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Zomosa-Signoret, Viviana, Jacques-Damien Arnaud, Pascaline Fontes, Maria-Terresa Alvarez-Martinez, and Jean-Pierre Liautard. "Physiological role of the cellular prion protein." Veterinary Research 39, no. 4 (November 27, 2007): 09. http://dx.doi.org/10.1051/vetres:2007048.
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Gidon-Jeangirard, Carole, Bénédicte Hugel, Vincent Holl, Florence Toti, Jean-Louis Laplanche, Dominique Meyer, and Jean-Marie Freyssinet. "Annexin V Delays Apoptosis While Exerting an External Constraint Preventing the Release of CD4+ and PrPc+ Membrane Particles in a Human T Lymphocyte Model." Journal of Immunology 162, no. 10 (May 15, 1999): 5712–18. http://dx.doi.org/10.4049/jimmunol.162.10.5712.
Повний текст джерелаАнотація:
Abstract Phosphatidylserine exposure in the exoplasmic leaflet of the plasma membrane is one of the early hallmarks of cells undergoing apoptosis. The shedding of membrane particles carrying Ags testifying to their tissue origin is another characteristic feature. Annexin V, a protein of as yet unknown specific physiologic function, presents a high Ca2+-dependent affinity for phosphatidylserine and forms two-dimensional arrays at the membrane surface. In this study, we report the delaying action of annexin V on apoptosis in the CEM human T cell line expressing CD4 and the normal cellular prion protein (PrPc), two Ags of particular relevance to cell degeneration and with different attachments to the membrane. The effect of annexin V was additive to that of z-Val-Ala-Asp-fluoromethyl ketone, a potent caspase inhibitor. Annexin V significantly reduced the degree of proteolytic activation of caspase-3, and totally blocked the release of CD4+ and PrPc+ membrane particles. z-Val-Ala-Asp-fluoromethyl ketone was a more powerful antagonist of caspase-3 processing, but prevented the shedding of CD4+ vesicles only partially and had no effect on that of PrPc+ ones. These results suggest that an external membrane constraint, such as that exerted by annexin V, has important consequences on the course of programmed cell death and on the dissemination of particular Ags. In vivo, annexin V had a significant protective effect against spleen weight loss in mice treated by an alkylating agent previously shown to induce lymphocyte apoptosis.
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Damberger, F. F., B. Christen, D. R. Perez, S. Hornemann, and K. Wuthrich. "Cellular prion protein conformation and function." Proceedings of the National Academy of Sciences 108, no. 42 (October 10, 2011): 17308–13. http://dx.doi.org/10.1073/pnas.1106325108.
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Roucou, Xavier, and Andr�a C. LeBlanc. "Cellular prion protein neuroprotective function: implications in prion diseases." Journal of Molecular Medicine 83, no. 1 (November 10, 2004): 3–11. http://dx.doi.org/10.1007/s00109-004-0605-5.
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BROWN, David R. "PrPSc-like prion protein peptide inhibits the function of cellular prion protein." Biochemical Journal 352, no. 2 (November 24, 2000): 511–18. http://dx.doi.org/10.1042/bj3520511.
Повний текст джерелаАнотація:
Mice lacking expression of the prion protein are protected against infection with prion disease. Neurodegeneration in prion disease requires the formation of the abnormal isoform of the prion protein (PrPSc) from host prion protein. Therefore expression of normal host prion protein is necessary for prion disease. In the present investigation, it was demonstrated that PrPSc and a peptide resembling PrPSc, PrP106–126, both bind to cellular prion protein at amino acid residues 112–119. Interaction between PrP106–126 and the prion protein strips the prion protein from cells. Direct interaction of PrP106–126 with the prion protein was found to make cells more susceptible to copper toxicity, inhibited copper uptake into cells and inhibited the superoxide dismutase-like activity of the prion protein. Direct inhibition of prion protein function by PrPSc may be necessary for neurodegeneration in prion disease.
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BROWN, David R. "PrPSc-like prion protein peptide inhibits the function of cellular prion protein." Biochemical Journal 352, no. 2 (December 1, 2000): 511. http://dx.doi.org/10.1042/0264-6021:3520511.
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Nguyen, Xuan T. A., Thanh Hoa Tran, Dan Cojoc, and Giuseppe Legname. "Copper Binding Regulates Cellular Prion Protein Function." Molecular Neurobiology 56, no. 9 (February 7, 2019): 6121–33. http://dx.doi.org/10.1007/s12035-019-1510-9.
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