Journal articles on the topic 'Cellular prion protein physiological function, Myelin'
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1
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.
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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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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.
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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.
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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.
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Go, Gyeongyun, and Sang Hun Lee. "The Cellular Prion Protein: A Promising Therapeutic Target for Cancer." International Journal of Molecular Sciences 21, no. 23 (December 2, 2020): 9208. http://dx.doi.org/10.3390/ijms21239208.
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Studies on the cellular prion protein (PrPC) have been actively conducted because misfolded PrPC is known to cause transmissible spongiform encephalopathies or prion disease. PrPC is a glycophosphatidylinositol-anchored cell surface glycoprotein that has been reported to affect several cellular functions such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation. Recently, it has also been reported that PrPC mediates tumor progression by enhancing the proliferation, metastasis, and drug resistance of cancer cells. In addition, PrPC regulates cancer stem cell properties by interacting with cancer stem cell marker proteins. In this review, we summarize how PrPC promotes tumor progression in terms of proliferation, metastasis, drug resistance, and cancer stem cell properties. In addition, we discuss strategies to treat tumors by modulating the function and expression of PrPC via the regulation of HSPA1L/HIF-1α expression and using an anti-prion antibody.
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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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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.
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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.
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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.
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Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrPC) of the host. PrPCis necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrPC, and therefore, understanding the physiological role of PrPCmay help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics.
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Henzi, Anna, and Adriano Aguzzi. "The prion protein is not required for peripheral nerve de- and remyelination after crush injury." PLOS ONE 16, no. 1 (January 22, 2021): e0245944. http://dx.doi.org/10.1371/journal.pone.0245944.
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The cellular prion protein (PrP) is essential to the long-term maintenance of myelin sheaths in peripheral nerves. PrP activates the adhesion G-protein coupled receptor Adgrg6 on Schwann cells and initiates a pro-myelination cascade of molecular signals. Because Adgrg6 is crucial for peripheral myelin development and regeneration after nerve injury, we investigated the role of PrP in peripheral nerve repair. We performed experimental sciatic nerve crush injuries in co-isogenic wild-type and PrP-deficient mice, and examined peripheral nerve repair processes. Generation of repair Schwann cells, macrophage recruitment and remyelination were similar in PrP-deficient and wild-type mice. We conclude that PrP is dispensable for sciatic nerve de- and remyelination after crush injury. Adgrg6 may sustain its function in peripheral nerve repair independently of its activation by PrP.
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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.
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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+.
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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.
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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.
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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.
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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.
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Caldarulo, Enrico, Alessandro Barducci, Kurt Wüthrich, and Michele Parrinello. "Prion protein β2–α2 loop conformational landscape." Proceedings of the National Academy of Sciences 114, no. 36 (August 21, 2017): 9617–22. http://dx.doi.org/10.1073/pnas.1712155114.
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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.
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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.
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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.
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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.
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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.
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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.
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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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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.
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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.
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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.
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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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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.
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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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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.
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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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Gonzalez-Gronow, Mario, and Salvatore Vincent Pizzo. "Physiological Roles of the Autoantibodies to the 78-Kilodalton Glucose-Regulated Protein (GRP78) in Cancer and Autoimmune Diseases." Biomedicines 10, no. 6 (May 24, 2022): 1222. http://dx.doi.org/10.3390/biomedicines10061222.
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The 78 kDa glucose-regulated protein (GRP78), a member of the 70 kDa heat-shock family of molecular chaperones (HSP70), is essential for the regulation of the unfolded protein response (UPR) resulting from cellular endoplasmic reticulum (ER) stress. During ER stress, GRP78 evades retention mechanisms and is translocated to the cell surface (csGRP78) where it functions as an autoantigen. Autoantibodies to GRP78 appear in prostate, ovarian, gastric, malignant melanoma, and colorectal cancers. They are also found in autoimmune pathologies such as rheumatoid arthritis (RA), neuromyelitis optica (NMO), anti-myelin oligodendrocyte glycoprotein antibody-associated disorder (AMOGAD), Lambert-Eaton myasthenic syndrome (LEMS), multiple sclerosis (MS), neuropsychiatric systemic lupus erythematosus (NPSLE) and type 1 diabetes (T1D). In NMO, MS, and NPSLE these autoantibodies disrupt and move across the blood-brain barrier (BBB), facilitating their entry and that of other pathogenic antibodies to the brain. Although csGRP78 is common in both cancer and autoimmune diseases, there are major differences in the specificity of its autoantibodies. Here, we discuss how ER mechanisms modulate csGRP78 antigenicity and the production of autoantibodies, permitting this chaperone to function as a dual compartmentalized receptor with independent signaling pathways that promote either pro-proliferative or apoptotic signaling, depending on whether the autoantibodies bind csGRP78 N- or C-terminal regions.
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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.
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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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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.
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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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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.
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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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Soukup, Alexandra, Kirby D. Johnson, Daniel J. Conn, Evgenia Shishkova, Koichi Ricardo Katsumura, Peng Liu, Erik A. Ranheim, et al. "GATA2-Dependent Developmental and Regenerative Networks." Blood 134, Supplement_1 (November 13, 2019): 1182. http://dx.doi.org/10.1182/blood-2019-126875.
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Coding and regulatory human GATA2 mutations that deregulate protein expression and/or function cause immunodeficiency that often progresses to MDS/AML (McReynolds et al., 2018). In the mouse, decreased GATA2 expression impairs hematopoietic stem/progenitor cell (HSPC) genesis and function (de Pater et al., 2013; Gao et al., 2013; Tsai et al., 1994). While prior studies demonstrated Gata2 +9.5 and -77 enhancers are essential for HSC emergence (+9.5) and/or progenitor cell fate (+9.5 and -77) (Johnson et al., 2012; Johnson et al., 2015; Mehta et al., 2017) and hematopoietic regeneration (+9.5) (Soukup et al., 2019), the mechanisms mediating these processes are not completely established. The -77 enhancer is required for fetal liver progenitors to undergo erythroid, megakaryocytic, granulocytic and monocytic differentiation. By contrast, progenitors with a -77 homozygous deletion (-77-/-) exhibit a predominant monocytic cell fate and generate macrophages ex vivo (Johnson et al., 2015). Using multiomic and single-cell strategies, we asked how this enhancer orchestrates a balance between fate-promoting and -suppressing circuitry in cell populations and single cells. Quantitative proteomics was conducted to discover the -77-regulated protein ensemble conferring multiple fates in a myeloid progenitor population [Common Myeloid Progenitor (CMP) and Granulocyte-Monocyte Progenitor (GMP)] from E14.5 fetal liver of -77+/+ and -77-/- mouse embryos. -77-/- progenitors exhibited decreased levels of GATA2 (4.7-fold) and proteins generated from GATA2 target genes (GATA1: 51-fold; HDC: 52-fold). The 202 proteins upregulated in -77-/- progenitors highlighted immune and inflammatory mechanisms, while the 232 downregulated proteins were linked to erythroid, megakaryocyte and granulocyte biology, indicative of loss of these fate potentials. Innate immune machinery was upregulated in -77-/- vs. -77+/+ progenitors, including interferon (IFN) signaling pathway components such as the IFN-inducible transcription factor and critical monocytic differentiation determinant Interferon Regulatory Factor 8 (IRF8; 2.7 fold higher) (Kurotaki et al., 2013) and diverse pathogen sensors. Expressing GATA2 at physiological levels in -77-/- progenitors normalized the aberrant transcriptome. Since -77 deletion downregulated Gata2 and upregulated Irf8, we tested whether this opposing expression pattern occurs in distinct and/or identical cells in the population using single cell transcriptomics. -77 deletion decreased Gata2 expression, which was anti-correlative with Irf8, and detailed single cell analyses indicated that -77 loss downregulates GATA2, corrupting the transcriptome/proteome, Irf8 expression increases, and IRF8 enables or drives the predominant monocytic differentiation. To determine how GATA2-dependent mechanisms governing progenitor fate relate to those guiding HSPC expansion and differentiation during regeneration, we utilized our +9.5 human disease Ets motif mutation that abrogates myeloablation-dependent GATA2 induction and hematopoietic regeneration in bone marrow (Soukup et al., 2019). While population RNA-seq with Lin-Sca1+c-Kit+ (LSK) cells revealed little to no perturbations in the steady-state, 5-FU treatment of mutants led to altered expression of only 14% of the transcripts regulated in regenerating wild type cells (423/2974). Gene Ontology analysis of differentially expressed genes indicated that genes dysregulated by the Ets motif mutation included those linked to cell cycle regulation and cellular proliferation. As LSKs consist of LT-HSCs, ST-HSCs, and MPPs, we used single-cell transcriptomics to elucidate defective regenerative circuits in individual cells. Analysis of 17000-20000 wild type and mutant LSK cells revealed GATA2-dependent mechanisms distinct from those mediating progenitor cell fate control in the fetal liver. These studies have revealed context-dependent GATA2 mechanisms governing developmental and regenerative hematopoiesis, which will enable the development of strategies to detect, diagnose, and treat GATA2-linked blood diseases. Disclosures No relevant conflicts of interest to declare.
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Tsutsui, Shigeki, Megan Morgan, Hugo Tedford, Haitao You, Gerald W. Zamponi, and Peter K. Stys. "Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner." Molecular Brain 15, no. 1 (July 26, 2022). http://dx.doi.org/10.1186/s13041-022-00955-2.
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AbstractAs in neurons, CNS myelin expresses N-Methyl-D-Aspartate Receptors (NMDARs) that subserve physiological roles, but have the potential to induce injury to this vital element. Using 2-photon imaging of myelinic Ca in live ex vivo mouse optic nerves, we show that Cu ions potently modulate Ca levels in an NMDAR-dependent manner. Chelating Cu in the perfusate induced a substantial increase in Ca levels, and also caused significant axo-myelinic injury. Myelinic NMDARs are shown to be regulated by cellular prion protein; only in prion protein KO optic nerves does application of NMDA + D-serine induce a large Ca increase, consistent with strong desensitization of these receptors in the presence of prion protein limiting Ca overload. Aβ1-42 peptide induced a large Ca increase that was also Cu-dependent, and was blocked by NMDAR antagonism. Our results indicate that like in neurons, myelinic NMDARs permeate potentially injurious amounts of Ca, and are also potently regulated by micromolar Cu and activated by Aβ1-42 peptides. These findings shed mechanistic light on the important primary white matter injury frequently observed in Alzheimer's brain.
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Didonna, Alessandro. "Prion protein and its role in signal transduction." Cellular and Molecular Biology Letters 18, no. 2 (January 1, 2013). http://dx.doi.org/10.2478/s11658-013-0085-0.
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AbstractPrion diseases are a class of fatal neurodegenerative disorders that can be sporadic, genetic or iatrogenic. They are characterized by the unique nature of their etiologic agent: prions (PrPSc). A prion is an infectious protein with the ability to convert the host-encoded cellular prion protein (PrPC) into new prion molecules by acting as a template. Since Stanley B. Prusiner proposed the “protein-only” hypothesis for the first time, considerable effort has been put into defining the role played by PrPC in neurons. However, its physiological function remains unclear. This review summarizes the major findings that support the involvement of PrPC in signal transduction.
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Schneider, Benoit, Anne Baudry, Mathéa Pietri, Aurélie Alleaume-Butaux, Chloé Bizingre, Pierre Nioche, Odile Kellermann, and Jean-Marie Launay. "The Cellular Prion Protein—ROCK Connection: Contribution to Neuronal Homeostasis and Neurodegenerative Diseases." Frontiers in Cellular Neuroscience 15 (April 12, 2021). http://dx.doi.org/10.3389/fncel.2021.660683.
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Amyloid-based neurodegenerative diseases such as prion, Alzheimer's, and Parkinson's diseases have distinct etiologies and clinical manifestations, but they share common pathological events. These diseases are caused by abnormally folded proteins (pathogenic prions PrPSc in prion diseases, β-amyloids/Aβ and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease) that display β-sheet-enriched structures, propagate and accumulate in the nervous central system, and trigger neuronal death. In prion diseases, PrPSc-induced corruption of the physiological functions exerted by normal cellular prion proteins (PrPC) present at the cell surface of neurons is at the root of neuronal death. For a decade, PrPC emerges as a common cell surface receptor for other amyloids such as Aβ and α-synuclein, which relays, at least in part, their toxicity. In lipid-rafts of the plasma membrane, PrPC exerts a signaling function and controls a set of effectors involved in neuronal homeostasis, among which are the RhoA-associated coiled-coil containing kinases (ROCKs). Here we review (i) how PrPC controls ROCKs, (ii) how PrPC-ROCK coupling contributes to neuronal homeostasis, and (iii) how the deregulation of the PrPC-ROCK connection in amyloid-based neurodegenerative diseases triggers a loss of neuronal polarity, affects neurotransmitter-associated functions, contributes to the endoplasmic reticulum stress cascade, renders diseased neurons highly sensitive to neuroinflammation, and amplifies the production of neurotoxic amyloids.
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Gielnik, Maciej, Michał Taube, Lilia Zhukova, Igor Zhukov, Sebastian K. T. S. Wärmländer, Željko Svedružić, Wojciech M. Kwiatek, Astrid Gräslund, and Maciej Kozak. "Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein." Scientific Reports 11, no. 1 (November 4, 2021). http://dx.doi.org/10.1038/s41598-021-00495-0.
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AbstractThe cellular prion protein (PrPC) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrPC can undergo a structural transition into a toxic, β-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrPC binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrPC and Zn(II) ions. Binding of a single Zn(II) ion to the PrPC N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal α-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrPC can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrPC.
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Matamoros-Angles, A., A. Hervera, J. Soriano, E. Martí, P. Carulla, F. Llorens, M. Nuvolone, et al. "Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability." BMC Biology 20, no. 1 (January 13, 2022). http://dx.doi.org/10.1186/s12915-021-01203-0.
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Abstract Background Cellular prion protein (PrPC) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrPC in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrPC is expressed in a number of tissues, including at high levels in the nervous system, especially in neurons and glial cells, and while previous studies have established a neuroprotective role, conflicting evidence for a synaptic function has revealed both reduced and enhanced long-term potentiation, and variable observations on memory, learning, and behavior. Such evidence has been confounded by the absence of an appropriate knock-out mouse model to dissect the biological relevance of PrPC, with some functions recently shown to be misattributed to PrPC due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrPC in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp0/0 mouse model (PrnpZH3/ZH3). Results We performed behavioral and operant conditioning tests to evaluate memory and learning capabilities, with results showing decreased motility, impaired operant conditioning learning, and anxiety-related behavior in PrnpZH3/ZH3 animals. We also carried in vivo electrophysiological recordings on CA3-CA1 synapses in living behaving mice and monitored spontaneous neuronal firing and network formation in primary neuronal cultures of PrnpZH3/ZH3 vs wildtype mice. PrPC absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the PrnpZH3/ZH3 hippocampus. In addition, we observed a delay in neuronal maturation and network formation in PrnpZH3/ZH3 cultures. Conclusion Our results demonstrate that PrPC promotes neuronal network formation and connectivity. PrPC mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.
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Bosch, Assumpció, and Raúl Estévez. "Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy." Frontiers in Cellular Neuroscience 14 (January 22, 2021). http://dx.doi.org/10.3389/fncel.2020.627887.
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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder belonging to the group of vacuolating leukodystrophies. It is characterized by megalencephaly, loss of motor functions, epilepsy, and mild mental decline. In brain biopsies of MLC patients, vacuoles were observed in myelin and in astrocytes surrounding blood vessels. It is mainly caused by recessive mutations in MLC1 and HEPACAM (also called GLIALCAM) genes. These disease variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. Besides, dominant mutations in HEPACAM were also identified in a subtype of MLC patients (MLC2B) with a remitting phenotype. MLC1 and GlialCAM proteins form a complex mainly expressed in brain astrocytes at the gliovascular interface and in Bergmann glia at the cerebellum. Both proteins regulate several ion channels and transporters involved in the control of ion and water fluxes in glial cells, either directly influencing their location and function, or indirectly regulating associated signal transduction pathways. However, the MLC1/GLIALCAM complex function and the related pathological mechanisms leading to MLC are still unknown. It has been hypothesized that, in MLC, the role of glial cells in brain ion homeostasis is altered in both physiological and inflammatory conditions. There is no therapy for MLC patients, only supportive treatment. As MLC2B patients show an MLC reversible phenotype, we speculated that the phenotype of MLC1 and MLC2A patients could also be mitigated by the re-introduction of the correct gene even at later stages. To prove this hypothesis, we injected in the cerebellar subarachnoid space of Mlc1 knockout mice an adeno-associated virus (AAV) coding for human MLC1 under the control of the glial-fibrillary acidic protein promoter. MLC1 expression in the cerebellum extremely reduced myelin vacuolation at all ages in a dose-dependent manner. This study could be considered as the first preclinical approach for MLC. We also suggest other potential therapeutic strategies in this review.
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Corraliza-Gomez, Miriam, Beatriz Bendito, David Sandonis-Camarero, Jorge Mondejar-Duran, Miguel Villa, Marta Poncela, Jorge Valero, Diego Sanchez, and Maria D. Ganfornina. "Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses." Frontiers in Cellular Neuroscience 17 (January 26, 2023). http://dx.doi.org/10.3389/fncel.2023.1112930.
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Microglial cells are recognized as very dynamic brain cells, screening the environment and sensitive to signals from all other cell types in health and disease. Apolipoprotein D (ApoD), a lipid-binding protein of the Lipocalin family, is required for nervous system optimal function and proper development and maintenance of key neural structures. ApoD has a cell and state-dependent expression in the healthy nervous system, and increases its expression upon aging, damage or neurodegeneration. An extensive overlap exists between processes where ApoD is involved and those where microglia have an active role. However, no study has analyzed the role of ApoD in microglial responses. In this work, we test the hypothesis that ApoD, as an extracellular signal, participates in the intercellular crosstalk sensed by microglia and impacts their responses upon physiological aging or damaging conditions. We find that a significant proportion of ApoD-dependent aging transcriptome are microglia-specific genes, and show that lack of ApoD in vivo dysregulates microglial density in mouse hippocampus in an age-dependent manner. Murine BV2 and primary microglia do not express ApoD, but it can be internalized and targeted to lysosomes, where unlike other cell types it is transiently present. Cytokine secretion profiles and myelin phagocytosis reveal that ApoD has both long-term pre-conditioning effects on microglia as well as acute effects on these microglial immune functions, without significant modification of cell survival. ApoD-triggered cytokine signatures are stimuli (paraquat vs. Aβ oligomers) and sex-dependent. Acute exposure to ApoD induces microglia to switch from their resting state to a secretory and less phagocytic phenotype, while long-term absence of ApoD leads to attenuated cytokine induction and increased myelin uptake, supporting a role for ApoD as priming or immune training factor. This knowledge should help to advance our understanding of the complex responses of microglia during aging and neurodegeneration, where signals received along our lifespan are combined with damage-triggered acute signals, conditioning both beneficial roles and limitations of microglial functions.
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Baena-Montes, Jara M., Sahar Avazzadeh, and Leo R. Quinlan. "α-synuclein pathogenesis in hiPSC models of Parkinson’s disease." Neuronal Signaling 5, no. 2 (June 2021). http://dx.doi.org/10.1042/ns20210021.
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Abstract α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic (DA) neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies (DLB) and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient’s genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focuses on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.