Neurodegeneration and unfolded-protein response in mice expressing a membrane-tethered flexible tail of PrP
The cellular prion protein (PrPC) consists of a flexible N-terminal tail (FT, aa 23-128) hinged to a membrane-anchored globular domain (GD, aa 129-231). Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore,...
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| Veröffentlicht in: | PloS one 2015-02, Vol.10 (2), p.e0117412 |
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| creator | Dametto, Paolo Lakkaraju, Asvin K K Bridel, Claire Villiger, Lukas O'Connor, Tracy Herrmann, Uli S Pelczar, Pawel Rülicke, Thomas McHugh, Donal Adili, Arlind Aguzzi, Adriano |
| description | The cellular prion protein (PrPC) consists of a flexible N-terminal tail (FT, aa 23-128) hinged to a membrane-anchored globular domain (GD, aa 129-231). Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrPΔ141-225, or "FTgpi"). Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection. |
| doi_str_mv | 10.1371/journal.pone.0117412 |
| format | Article |
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Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrPΔ141-225, or "FTgpi"). Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0117412</identifier><identifier>PMID: 25658480</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Allosteric properties ; Alzheimer's disease ; Animal sciences ; Animals ; Antibodies ; Cerebellum - metabolism ; Cerebellum - pathology ; Clonal deletion ; Deactivation ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress ; Genetic engineering ; Hospitals ; Immunoglobulins ; Inactivation ; Laboratory animals ; Mice ; Mice, Transgenic ; Neurodegeneration ; Neuropathology ; Neurotoxicity ; Peptides ; Phosphorylation ; Prion Diseases - metabolism ; Prion Diseases - pathology ; Prion protein ; Prions ; Prions (Proteins) ; Protein expression ; Protein folding ; Proteins ; PrPC Proteins - analysis ; PrPC Proteins - metabolism ; Rodents ; Transgenic animals ; Transgenic mice ; Unfolded Protein Response ; Zoology</subject><ispartof>PloS one, 2015-02, Vol.10 (2), p.e0117412</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Dametto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Dametto et al 2015 Dametto et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-f9e045764b7d732f54c6f22d106a7727ff784641b3641d8a53793609cae00c393</citedby><cites>FETCH-LOGICAL-c692t-f9e045764b7d732f54c6f22d106a7727ff784641b3641d8a53793609cae00c393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319788/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319788/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25658480$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ma, Jiyan</contributor><creatorcontrib>Dametto, Paolo</creatorcontrib><creatorcontrib>Lakkaraju, Asvin K K</creatorcontrib><creatorcontrib>Bridel, Claire</creatorcontrib><creatorcontrib>Villiger, Lukas</creatorcontrib><creatorcontrib>O'Connor, Tracy</creatorcontrib><creatorcontrib>Herrmann, Uli S</creatorcontrib><creatorcontrib>Pelczar, Pawel</creatorcontrib><creatorcontrib>Rülicke, Thomas</creatorcontrib><creatorcontrib>McHugh, Donal</creatorcontrib><creatorcontrib>Adili, Arlind</creatorcontrib><creatorcontrib>Aguzzi, Adriano</creatorcontrib><title>Neurodegeneration and unfolded-protein response in mice expressing a membrane-tethered flexible tail of PrP</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The cellular prion protein (PrPC) consists of a flexible N-terminal tail (FT, aa 23-128) hinged to a membrane-anchored globular domain (GD, aa 129-231). Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrPΔ141-225, or "FTgpi"). Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection.</description><subject>Allosteric properties</subject><subject>Alzheimer's disease</subject><subject>Animal sciences</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Cerebellum - metabolism</subject><subject>Cerebellum - pathology</subject><subject>Clonal deletion</subject><subject>Deactivation</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress</subject><subject>Genetic engineering</subject><subject>Hospitals</subject><subject>Immunoglobulins</subject><subject>Inactivation</subject><subject>Laboratory animals</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Neurodegeneration</subject><subject>Neuropathology</subject><subject>Neurotoxicity</subject><subject>Peptides</subject><subject>Phosphorylation</subject><subject>Prion Diseases - metabolism</subject><subject>Prion Diseases - pathology</subject><subject>Prion protein</subject><subject>Prions</subject><subject>Prions (Proteins)</subject><subject>Protein expression</subject><subject>Protein folding</subject><subject>Proteins</subject><subject>PrPC Proteins - analysis</subject><subject>PrPC Proteins - metabolism</subject><subject>Rodents</subject><subject>Transgenic animals</subject><subject>Transgenic mice</subject><subject>Unfolded Protein Response</subject><subject>Zoology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkmuL1DAUhoso7rr6D0QLguCHjrk1ab4Iy-JlYHEXb19DpjnpZO00Y5LK-O_NON1lCgoSSA4nz3lPOHmL4ilGC0wFfn3jxzDofrH1AywQxoJhcq84xZKSihNE7x_FJ8WjGG8QqmnD-cPihNS8bliDTovvH2EM3kAHAwSdnB9KPZhyHKzvDZhqG3wCN5QBYm4UoczxxrVQwm6bc9ENXanLDWxWQQ9QJUhrCGBK28POrXook3Z96W15Ha4fFw-s7iM8mc6z4uu7t18uPlSXV--XF-eXVcslSZWVgFgtOFsJIyixNWu5JcRgxLUQRFgrGsYZXtG8mUbXVEjKkWw1INRSSc-K5wfdbe-jmuYUFeY1wVJSXGdieSCM1zdqG9xGh1_Ka6f-JHzolA7JtT0oAtQ0BGpJuGXSooblkFhEGoqp1m3WejN1G1cbMC0MKeh-Jjq_Gdxadf6nYhRL0TRZ4MUkEPyPEWL6x5MnqtP5VS7_TxZrNy626pwR2WBRC5ypxV-ovAzkX8tOsS7nZwWvZgWZSbBLnR5jVMvPn_6fvfo2Z18esWvQfVpH3497h8U5yA5gG3yMAezd5DBSe6PfTkPtja4mo-eyZ8dTvyu6dTb9DbTn-C4</recordid><startdate>20150206</startdate><enddate>20150206</enddate><creator>Dametto, Paolo</creator><creator>Lakkaraju, Asvin K K</creator><creator>Bridel, Claire</creator><creator>Villiger, Lukas</creator><creator>O'Connor, Tracy</creator><creator>Herrmann, Uli S</creator><creator>Pelczar, Pawel</creator><creator>Rülicke, Thomas</creator><creator>McHugh, Donal</creator><creator>Adili, Arlind</creator><creator>Aguzzi, Adriano</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150206</creationdate><title>Neurodegeneration and unfolded-protein response in mice expressing a membrane-tethered flexible tail of PrP</title><author>Dametto, Paolo ; Lakkaraju, Asvin K K ; Bridel, Claire ; Villiger, Lukas ; O'Connor, Tracy ; Herrmann, Uli S ; Pelczar, Pawel ; Rülicke, Thomas ; McHugh, Donal ; Adili, Arlind ; Aguzzi, Adriano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-f9e045764b7d732f54c6f22d106a7727ff784641b3641d8a53793609cae00c393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Allosteric properties</topic><topic>Alzheimer's disease</topic><topic>Animal sciences</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Cerebellum - metabolism</topic><topic>Cerebellum - pathology</topic><topic>Clonal deletion</topic><topic>Deactivation</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum Stress</topic><topic>Genetic engineering</topic><topic>Hospitals</topic><topic>Immunoglobulins</topic><topic>Inactivation</topic><topic>Laboratory animals</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Neurodegeneration</topic><topic>Neuropathology</topic><topic>Neurotoxicity</topic><topic>Peptides</topic><topic>Phosphorylation</topic><topic>Prion Diseases - metabolism</topic><topic>Prion Diseases - pathology</topic><topic>Prion protein</topic><topic>Prions</topic><topic>Prions (Proteins)</topic><topic>Protein expression</topic><topic>Protein folding</topic><topic>Proteins</topic><topic>PrPC Proteins - analysis</topic><topic>PrPC Proteins - metabolism</topic><topic>Rodents</topic><topic>Transgenic animals</topic><topic>Transgenic mice</topic><topic>Unfolded Protein Response</topic><topic>Zoology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dametto, Paolo</creatorcontrib><creatorcontrib>Lakkaraju, Asvin K K</creatorcontrib><creatorcontrib>Bridel, Claire</creatorcontrib><creatorcontrib>Villiger, Lukas</creatorcontrib><creatorcontrib>O'Connor, Tracy</creatorcontrib><creatorcontrib>Herrmann, Uli S</creatorcontrib><creatorcontrib>Pelczar, Pawel</creatorcontrib><creatorcontrib>Rülicke, Thomas</creatorcontrib><creatorcontrib>McHugh, Donal</creatorcontrib><creatorcontrib>Adili, Arlind</creatorcontrib><creatorcontrib>Aguzzi, Adriano</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrPΔ141-225, or "FTgpi"). Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25658480</pmid><doi>10.1371/journal.pone.0117412</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Allosteric properties Alzheimer's disease Animal sciences Animals Antibodies Cerebellum - metabolism Cerebellum - pathology Clonal deletion Deactivation Endoplasmic reticulum Endoplasmic Reticulum Stress Genetic engineering Hospitals Immunoglobulins Inactivation Laboratory animals Mice Mice, Transgenic Neurodegeneration Neuropathology Neurotoxicity Peptides Phosphorylation Prion Diseases - metabolism Prion Diseases - pathology Prion protein Prions Prions (Proteins) Protein expression Protein folding Proteins PrPC Proteins - analysis PrPC Proteins - metabolism Rodents Transgenic animals Transgenic mice Unfolded Protein Response Zoology |
| title | Neurodegeneration and unfolded-protein response in mice expressing a membrane-tethered flexible tail of PrP |
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