FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2004190654> ?p ?o ?g. }

• W2004190654 endingPage "26726" @default.
• W2004190654 startingPage "26719" @default.
• W2004190654 abstract "The mechanisms by which prions kill neurons and the role of the cellular prion protein in this process are enigmatic. Insight into these questions is provided by the neurodegenerative phenotypes of transgenic mice expressing prion protein (PrP) molecules with deletions of conserved amino acids in the central region. We report here that expression in transfected cells of the most toxic of these PrP deletion mutants (Δ105–125) induces large, spontaneous ionic currents that can be detected by patch-clamping techniques. These currents are produced by relatively non-selective, cation-permeable channels or pores in the cell membrane and can be silenced by overexpression of wild-type PrP, as well as by treatment with a sulfated glycosaminoglycan. Similar currents are induced by PrP molecules carrying several different point mutations in the central region that cause familial prion diseases in humans. The ionic currents described here are distinct from those produced in artificial lipid membranes by synthetic peptides derived from the PrP sequence because they are induced by membrane-anchored forms of PrP that are synthesized by cells and that are found in vivo. Our results indicate that the neurotoxicity of some mutant forms of PrP is attributable to enhanced ion channel activity and that wild-type PrP possesses a channel-silencing activity. Drugs that block PrP-associated channels or pores may therefore represent novel therapeutic agents for treatment of patients with prion diseases. The mechanisms by which prions kill neurons and the role of the cellular prion protein in this process are enigmatic. Insight into these questions is provided by the neurodegenerative phenotypes of transgenic mice expressing prion protein (PrP) molecules with deletions of conserved amino acids in the central region. We report here that expression in transfected cells of the most toxic of these PrP deletion mutants (Δ105–125) induces large, spontaneous ionic currents that can be detected by patch-clamping techniques. These currents are produced by relatively non-selective, cation-permeable channels or pores in the cell membrane and can be silenced by overexpression of wild-type PrP, as well as by treatment with a sulfated glycosaminoglycan. Similar currents are induced by PrP molecules carrying several different point mutations in the central region that cause familial prion diseases in humans. The ionic currents described here are distinct from those produced in artificial lipid membranes by synthetic peptides derived from the PrP sequence because they are induced by membrane-anchored forms of PrP that are synthesized by cells and that are found in vivo. Our results indicate that the neurotoxicity of some mutant forms of PrP is attributable to enhanced ion channel activity and that wild-type PrP possesses a channel-silencing activity. Drugs that block PrP-associated channels or pores may therefore represent novel therapeutic agents for treatment of patients with prion diseases. IntroductionPrion diseases are fatal neurodegenerative disorders in which a normal, cell surface glycoprotein called PrPC 2The abbreviations used are: PrPprion proteinPrPCcellular isoform of PrPPrPScscrapie isoform of PrPCRcentral regionPPSpentosan polysulfateNMDGN-methyl-d-glucamineTEAtetraethylammonium. is converted into PrPSc, a conformationally altered isoform that propagates itself by a molecular templating mechanism (1Prusiner S.B. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 13363-13383Crossref PubMed Scopus (5087) Google Scholar, 2Prusiner S.B. Prion Biology and Diseases. Second Ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York2004Google Scholar). Although much is now understood about how infectious prions propagate, the mechanisms by which neurotoxic forms of PrP kill nerve cells remain enigmatic (3Chiesa R. Harris D.A. Neurobiol. Dis. 2001; 8: 743-763Crossref PubMed Scopus (146) Google Scholar). Surprisingly, membrane-bound PrPC appears to play a crucial role in mediating the neurotoxicity of PrPSc. It has been proposed that interactions with PrPSc during the conversion process may alter a normal, physiological activity of PrPC, resulting in the transmission of a neurotoxic signal (4Harris D.A. True H.L. Neuron. 2006; 50: 353-357Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Thus, identifying the normal function of PrPC is important for understanding the mechanism of prion-induced neurodegeneration. However, the function of PrPC remains unclear because mice lacking this protein display no overt phenotype (5Büeler H. Fischer M. Lang Y. Bluethmann H. Lipp H.P. DeArmond S.J. Prusiner S.B. Aguet M. Weissmann C. Nature. 1992; 356: 577-582Crossref PubMed Scopus (1432) Google Scholar, 6Westergard L. Christensen H.M. Harris D.A. Biochim. Biophys. Acta. 2007; 1772: 629-644Crossref PubMed Scopus (292) Google Scholar).Insights into the physiological function of PrPC and how it might be subverted in the disease state have been provided by transgenic mice expressing forms of PrP missing conserved residues in the central region of the protein (7Baumann F. Pahnke J. Radovanovic I. Rülicke T. Bremer J. Tolnay M. Aguzzi A. PLoS One. 2009; 4e6707Crossref PubMed Scopus (25) Google Scholar, 8Shmerling D. Hegyi I. Fischer M. Blättler T. Brandner S. Götz J. Rülicke T. Flechsig E. Cozzio A. von Mering C. Hangartner C. Aguzzi A. Weissmann C. Cell. 1998; 93: 203-214Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar, 9Baumann F. Tolnay M. Brabeck C. Pahnke J. Kloz U. Niemann H.H. Heikenwalder M. Rülicke T. Bürkle A. Aguzzi A. EMBO J. 2007; 26: 538-547Crossref PubMed Scopus (191) Google Scholar, 10Li A. Christensen H.M. Stewart L.R. Roth K.A. Chiesa R. Harris D.A. EMBO J. 2007; 26: 548-558Crossref PubMed Scopus (175) Google Scholar). Each of these mice displays a neurodegenerative phenotype that is dose-dependently suppressed by co-expression of wild-type (WT) PrP, suggesting an antagonistic relationship between the normal activity of PrPC and the neurotoxic effects of the deletion mutants. We have found that mice expressing the smallest of the deletions (Δ105–125 or ΔCR for central region) display the most dramatic phenotype, characterized by neonatal lethality with massive degeneration of cerebellar granule neurons and vacuolar degeneration of white matter regions of the brain and spinal cord. ΔCR PrP is neither aggregated nor protease-resistant, and its cellular localization is identical to that of wild-type PrP (10Li A. Christensen H.M. Stewart L.R. Roth K.A. Chiesa R. Harris D.A. EMBO J. 2007; 26: 548-558Crossref PubMed Scopus (175) Google Scholar, 11Christensen H.M. Harris D.A. J. Neurochem. 2009; 108: 44-56Crossref PubMed Scopus (19) Google Scholar). Thus, the neurotoxicity of ΔCR PrP is likely to be due to an alteration in a physiological activity of PrPC rather than to the formation of PrPSc-like aggregates.We recently reported the unusual observation that cells expressing ΔCR PrP, as well as other toxic deletion mutants, are hypersensitive to killing by two classes of drugs normally used to select transfected cell lines (12Massignan T. Stewart R.S. Biasini E. Solomon I.H. Bonetto V. Chiesa R. Harris D.A. J. Biol. Chem. 2010; 285: 7752-7765Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). This effect, which was abolished by membrane depolarization, is likely due to enhanced cellular accumulation of these cationic drugs, possibly down an electrochemical gradient. These results suggested that the mutant PrPs might be altering the activity of membrane channels or transporters responsible for drug uptake.In the present study, we have employed patch-clamping techniques to test directly for a connection between ΔCR PrP and ion channel activity. We report the surprising observation that PrP molecules carrying deletions or disease-associated point mutations in the central region induce large, spontaneous currents when expressed in a variety of different cell types. We hypothesize that the ion channels or membrane pores underlying these currents play a critical role in the pathological effects of neurotoxic PrP mutants and that they represent a new class of potential drug targets for treatment of prion diseases. IntroductionPrion diseases are fatal neurodegenerative disorders in which a normal, cell surface glycoprotein called PrPC 2The abbreviations used are: PrPprion proteinPrPCcellular isoform of PrPPrPScscrapie isoform of PrPCRcentral regionPPSpentosan polysulfateNMDGN-methyl-d-glucamineTEAtetraethylammonium. is converted into PrPSc, a conformationally altered isoform that propagates itself by a molecular templating mechanism (1Prusiner S.B. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 13363-13383Crossref PubMed Scopus (5087) Google Scholar, 2Prusiner S.B. Prion Biology and Diseases. Second Ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York2004Google Scholar). Although much is now understood about how infectious prions propagate, the mechanisms by which neurotoxic forms of PrP kill nerve cells remain enigmatic (3Chiesa R. Harris D.A. Neurobiol. Dis. 2001; 8: 743-763Crossref PubMed Scopus (146) Google Scholar). Surprisingly, membrane-bound PrPC appears to play a crucial role in mediating the neurotoxicity of PrPSc. It has been proposed that interactions with PrPSc during the conversion process may alter a normal, physiological activity of PrPC, resulting in the transmission of a neurotoxic signal (4Harris D.A. True H.L. Neuron. 2006; 50: 353-357Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Thus, identifying the normal function of PrPC is important for understanding the mechanism of prion-induced neurodegeneration. However, the function of PrPC remains unclear because mice lacking this protein display no overt phenotype (5Büeler H. Fischer M. Lang Y. Bluethmann H. Lipp H.P. DeArmond S.J. Prusiner S.B. Aguet M. Weissmann C. Nature. 1992; 356: 577-582Crossref PubMed Scopus (1432) Google Scholar, 6Westergard L. Christensen H.M. Harris D.A. Biochim. Biophys. Acta. 2007; 1772: 629-644Crossref PubMed Scopus (292) Google Scholar).Insights into the physiological function of PrPC and how it might be subverted in the disease state have been provided by transgenic mice expressing forms of PrP missing conserved residues in the central region of the protein (7Baumann F. Pahnke J. Radovanovic I. Rülicke T. Bremer J. Tolnay M. Aguzzi A. PLoS One. 2009; 4e6707Crossref PubMed Scopus (25) Google Scholar, 8Shmerling D. Hegyi I. Fischer M. Blättler T. Brandner S. Götz J. Rülicke T. Flechsig E. Cozzio A. von Mering C. Hangartner C. Aguzzi A. Weissmann C. Cell. 1998; 93: 203-214Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar, 9Baumann F. Tolnay M. Brabeck C. Pahnke J. Kloz U. Niemann H.H. Heikenwalder M. Rülicke T. Bürkle A. Aguzzi A. EMBO J. 2007; 26: 538-547Crossref PubMed Scopus (191) Google Scholar, 10Li A. Christensen H.M. Stewart L.R. Roth K.A. Chiesa R. Harris D.A. EMBO J. 2007; 26: 548-558Crossref PubMed Scopus (175) Google Scholar). Each of these mice displays a neurodegenerative phenotype that is dose-dependently suppressed by co-expression of wild-type (WT) PrP, suggesting an antagonistic relationship between the normal activity of PrPC and the neurotoxic effects of the deletion mutants. We have found that mice expressing the smallest of the deletions (Δ105–125 or ΔCR for central region) display the most dramatic phenotype, characterized by neonatal lethality with massive degeneration of cerebellar granule neurons and vacuolar degeneration of white matter regions of the brain and spinal cord. ΔCR PrP is neither aggregated nor protease-resistant, and its cellular localization is identical to that of wild-type PrP (10Li A. Christensen H.M. Stewart L.R. Roth K.A. Chiesa R. Harris D.A. EMBO J. 2007; 26: 548-558Crossref PubMed Scopus (175) Google Scholar, 11Christensen H.M. Harris D.A. J. Neurochem. 2009; 108: 44-56Crossref PubMed Scopus (19) Google Scholar). Thus, the neurotoxicity of ΔCR PrP is likely to be due to an alteration in a physiological activity of PrPC rather than to the formation of PrPSc-like aggregates.We recently reported the unusual observation that cells expressing ΔCR PrP, as well as other toxic deletion mutants, are hypersensitive to killing by two classes of drugs normally used to select transfected cell lines (12Massignan T. Stewart R.S. Biasini E. Solomon I.H. Bonetto V. Chiesa R. Harris D.A. J. Biol. Chem. 2010; 285: 7752-7765Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). This effect, which was abolished by membrane depolarization, is likely due to enhanced cellular accumulation of these cationic drugs, possibly down an electrochemical gradient. These results suggested that the mutant PrPs might be altering the activity of membrane channels or transporters responsible for drug uptake.In the present study, we have employed patch-clamping techniques to test directly for a connection between ΔCR PrP and ion channel activity. We report the surprising observation that PrP molecules carrying deletions or disease-associated point mutations in the central region induce large, spontaneous currents when expressed in a variety of different cell types. We hypothesize that the ion channels or membrane pores underlying these currents play a critical role in the pathological effects of neurotoxic PrP mutants and that they represent a new class of potential drug targets for treatment of prion diseases." @default.
• W2004190654 created "2016-06-24" @default.
• W2004190654 creator A5002859044 @default.
• W2004190654 creator A5032728621 @default.
• W2004190654 creator A5090309926 @default.
• W2004190654 date "2010-08-01" @default.
• W2004190654 modified "2023-09-30" @default.
• W2004190654 title "Neurotoxic Mutants of the Prion Protein Induce Spontaneous Ionic Currents in Cultured Cells" @default.
• W2004190654 cites W1520668014 @default.
• W2004190654 cites W1557182452 @default.
• W2004190654 cites W1709344386 @default.
• W2004190654 cites W1845629226 @default.
• W2004190654 cites W1966382960 @default.
• W2004190654 cites W1972409470 @default.
• W2004190654 cites W1978195237 @default.
• W2004190654 cites W1987268193 @default.
• W2004190654 cites W1990833847 @default.
• W2004190654 cites W1992380356 @default.
• W2004190654 cites W1998038512 @default.
• W2004190654 cites W1998955425 @default.
• W2004190654 cites W2000966016 @default.
• W2004190654 cites W2002280328 @default.
• W2004190654 cites W2006918309 @default.
• W2004190654 cites W2008004502 @default.
• W2004190654 cites W2015401740 @default.
• W2004190654 cites W2020258831 @default.
• W2004190654 cites W2021719065 @default.
• W2004190654 cites W2022957293 @default.
• W2004190654 cites W2024478381 @default.
• W2004190654 cites W2025546736 @default.
• W2004190654 cites W2030103154 @default.
• W2004190654 cites W2047690397 @default.
• W2004190654 cites W2053782362 @default.
• W2004190654 cites W2054088381 @default.
• W2004190654 cites W2058368188 @default.
• W2004190654 cites W2058602000 @default.
• W2004190654 cites W2060851302 @default.
• W2004190654 cites W2065471991 @default.
• W2004190654 cites W2066792035 @default.
• W2004190654 cites W2070160124 @default.
• W2004190654 cites W2071509261 @default.
• W2004190654 cites W2077060302 @default.
• W2004190654 cites W2099970570 @default.
• W2004190654 cites W2102427988 @default.
• W2004190654 cites W2105134519 @default.
• W2004190654 cites W2113792335 @default.
• W2004190654 cites W2116647726 @default.
• W2004190654 cites W2117548399 @default.
• W2004190654 cites W2128057594 @default.
• W2004190654 cites W2130547480 @default.
• W2004190654 cites W2149247478 @default.
• W2004190654 cites W2151541409 @default.
• W2004190654 cites W2152419135 @default.
• W2004190654 cites W2158707059 @default.
• W2004190654 cites W2158789551 @default.
• W2004190654 cites W2159808292 @default.
• W2004190654 cites W2165491779 @default.
• W2004190654 cites W2171526610 @default.
• W2004190654 cites W2171825278 @default.
• W2004190654 cites W2187608003 @default.
• W2004190654 cites W2324660492 @default.
• W2004190654 doi "https://doi.org/10.1074/jbc.m110.134619" @default.
• W2004190654 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2924115" @default.
• W2004190654 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20573963" @default.
• W2004190654 hasPublicationYear "2010" @default.
• W2004190654 type Work @default.
• W2004190654 sameAs 2004190654 @default.
• W2004190654 citedByCount "63" @default.
• W2004190654 countsByYear W20041906542012 @default.
• W2004190654 countsByYear W20041906542013 @default.
• W2004190654 countsByYear W20041906542014 @default.
• W2004190654 countsByYear W20041906542015 @default.
• W2004190654 countsByYear W20041906542016 @default.
• W2004190654 countsByYear W20041906542017 @default.
• W2004190654 countsByYear W20041906542018 @default.
• W2004190654 countsByYear W20041906542019 @default.
• W2004190654 countsByYear W20041906542020 @default.
• W2004190654 countsByYear W20041906542021 @default.
• W2004190654 countsByYear W20041906542022 @default.
• W2004190654 countsByYear W20041906542023 @default.
• W2004190654 crossrefType "journal-article" @default.
• W2004190654 hasAuthorship W2004190654A5002859044 @default.
• W2004190654 hasAuthorship W2004190654A5032728621 @default.
• W2004190654 hasAuthorship W2004190654A5090309926 @default.
• W2004190654 hasBestOaLocation W20041906541 @default.
• W2004190654 hasConcept C104317684 @default.
• W2004190654 hasConcept C12554922 @default.
• W2004190654 hasConcept C142724271 @default.
• W2004190654 hasConcept C143065580 @default.
• W2004190654 hasConcept C185592680 @default.
• W2004190654 hasConcept C2779134260 @default.
• W2004190654 hasConcept C3019804061 @default.
• W2004190654 hasConcept C55493867 @default.
• W2004190654 hasConcept C71924100 @default.
• W2004190654 hasConcept C86803240 @default.
• W2004190654 hasConcept C95444343 @default.
• W2004190654 hasConceptScore W2004190654C104317684 @default.
• W2004190654 hasConceptScore W2004190654C12554922 @default.

• next