α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication
The precise molecular mechanism of how misfolded α-synuclein (α-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrP C ) in mediating the uptake and the spread of recombinant α-Syn amyloids. The in vitro data revealed that the...
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| creator | Aulić, Suzana Masperone, Lara Narkiewicz, Joanna Isopi, Elisa Bistaffa, Edoardo Ambrosetti, Elena Pastore, Beatrice De Cecco, Elena Scaini, Denis Zago, Paola Moda, Fabio Tagliavini, Fabrizio Legname, Giuseppe |
| description | The precise molecular mechanism of how misfolded α-synuclein (α-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrP
C
) in mediating the uptake and the spread of recombinant α-Syn amyloids. The
in vitro
data revealed that the presence of PrP
C
fosters the higher uptake of α-Syn amyloid fibrils, which was also confirmed
in vivo
in wild type (
Prnp
+/+
) compared to PrP knock-out (
Prnp
−/−
) mice. Additionally, the presence of α-Syn amyloids blocked the replication of scrapie prions (PrP
Sc
)
in vitro
and
ex vivo
, indicating a link between the two proteins. Indeed, whilst PrP
C
is mediating the internalization of α-Syn amyloids, PrP
Sc
is not able to replicate in their presence. This observation has pathological relevance, since several reported case studies show that the accumulation of α-Syn amyloid deposits in Creutzfeldt-Jakob disease patients is accompanied by a longer disease course. |
| doi_str_mv | 10.1038/s41598-017-10236-x |
| format | Article |
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C
) in mediating the uptake and the spread of recombinant α-Syn amyloids. The
in vitro
data revealed that the presence of PrP
C
fosters the higher uptake of α-Syn amyloid fibrils, which was also confirmed
in vivo
in wild type (
Prnp
+/+
) compared to PrP knock-out (
Prnp
−/−
) mice. Additionally, the presence of α-Syn amyloids blocked the replication of scrapie prions (PrP
Sc
)
in vitro
and
ex vivo
, indicating a link between the two proteins. Indeed, whilst PrP
C
is mediating the internalization of α-Syn amyloids, PrP
Sc
is not able to replicate in their presence. This observation has pathological relevance, since several reported case studies show that the accumulation of α-Syn amyloid deposits in Creutzfeldt-Jakob disease patients is accompanied by a longer disease course.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-017-10236-x</identifier><identifier>PMID: 28855681</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 14 ; 14/19 ; 631/337/470/2284 ; 631/378/1689/364 ; 82/103 ; 82/83 ; alpha-Synuclein - genetics ; alpha-Synuclein - metabolism ; Amyloid ; Amyloid - administration & dosage ; Amyloid - genetics ; Amyloid - metabolism ; Animals ; Brain - metabolism ; Brain - pathology ; Cell Line, Tumor ; Cell spreading ; Creutzfeldt-Jakob disease ; Creutzfeldt-Jakob Syndrome - genetics ; Creutzfeldt-Jakob Syndrome - metabolism ; Creutzfeldt-Jakob Syndrome - pathology ; Endopeptidase K - chemistry ; Fibrils ; Gene Expression Regulation ; Humanities and Social Sciences ; Humans ; Injections, Intraventricular ; Internalization ; Mice ; Mice, Knockout ; multidisciplinary ; Neurons - metabolism ; Neurons - pathology ; Prion protein ; Prion Proteins - genetics ; Prion Proteins - metabolism ; Protein Binding ; Protein Transport ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Replication ; Rodents ; Science ; Science (multidisciplinary) ; Scrapie ; Signal Transduction ; Stereotaxic Techniques ; Synuclein ; Tyrosine 3-Monooxygenase - genetics ; Tyrosine 3-Monooxygenase - metabolism</subject><ispartof>Scientific reports, 2017-08, Vol.7 (1), p.10050-12, Article 10050</ispartof><rights>The Author(s) 2017</rights><rights>2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-f526fcd3148cd8ba961b059cd9975cb02b221d35a2c17ac486fa6d6f21f054253</citedby><cites>FETCH-LOGICAL-c474t-f526fcd3148cd8ba961b059cd9975cb02b221d35a2c17ac486fa6d6f21f054253</cites><orcidid>0000-0003-0716-4393</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577263/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577263/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28855681$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aulić, Suzana</creatorcontrib><creatorcontrib>Masperone, Lara</creatorcontrib><creatorcontrib>Narkiewicz, Joanna</creatorcontrib><creatorcontrib>Isopi, Elisa</creatorcontrib><creatorcontrib>Bistaffa, Edoardo</creatorcontrib><creatorcontrib>Ambrosetti, Elena</creatorcontrib><creatorcontrib>Pastore, Beatrice</creatorcontrib><creatorcontrib>De Cecco, Elena</creatorcontrib><creatorcontrib>Scaini, Denis</creatorcontrib><creatorcontrib>Zago, Paola</creatorcontrib><creatorcontrib>Moda, Fabio</creatorcontrib><creatorcontrib>Tagliavini, Fabrizio</creatorcontrib><creatorcontrib>Legname, Giuseppe</creatorcontrib><title>α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The precise molecular mechanism of how misfolded α-synuclein (α-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrP
C
) in mediating the uptake and the spread of recombinant α-Syn amyloids. The
in vitro
data revealed that the presence of PrP
C
fosters the higher uptake of α-Syn amyloid fibrils, which was also confirmed
in vivo
in wild type (
Prnp
+/+
) compared to PrP knock-out (
Prnp
−/−
) mice. Additionally, the presence of α-Syn amyloids blocked the replication of scrapie prions (PrP
Sc
)
in vitro
and
ex vivo
, indicating a link between the two proteins. Indeed, whilst PrP
C
is mediating the internalization of α-Syn amyloids, PrP
Sc
is not able to replicate in their presence. This observation has pathological relevance, since several reported case studies show that the accumulation of α-Syn amyloid deposits in Creutzfeldt-Jakob disease patients is accompanied by a longer disease course.</description><subject>13/1</subject><subject>14</subject><subject>14/19</subject><subject>631/337/470/2284</subject><subject>631/378/1689/364</subject><subject>82/103</subject><subject>82/83</subject><subject>alpha-Synuclein - genetics</subject><subject>alpha-Synuclein - metabolism</subject><subject>Amyloid</subject><subject>Amyloid - administration & dosage</subject><subject>Amyloid - genetics</subject><subject>Amyloid - metabolism</subject><subject>Animals</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell spreading</subject><subject>Creutzfeldt-Jakob disease</subject><subject>Creutzfeldt-Jakob Syndrome - genetics</subject><subject>Creutzfeldt-Jakob Syndrome - metabolism</subject><subject>Creutzfeldt-Jakob Syndrome - pathology</subject><subject>Endopeptidase K - chemistry</subject><subject>Fibrils</subject><subject>Gene Expression Regulation</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Injections, Intraventricular</subject><subject>Internalization</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>multidisciplinary</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Prion protein</subject><subject>Prion Proteins - genetics</subject><subject>Prion Proteins - metabolism</subject><subject>Protein Binding</subject><subject>Protein Transport</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>Replication</subject><subject>Rodents</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Scrapie</subject><subject>Signal Transduction</subject><subject>Stereotaxic Techniques</subject><subject>Synuclein</subject><subject>Tyrosine 3-Monooxygenase - genetics</subject><subject>Tyrosine 3-Monooxygenase - metabolism</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1UcuKFDEULcTBGWbmB1xIgRsXRvOu1EYYm3kIA4qj65BKUm3adNImKZkGf8of8ZtMd49NK5hF7iXn3JNzOU3zFMFXCBLxOlPEegEg6gCCmHBw_6g5wZAygAnGjw_64-Y85wWsh-Geov5Jc4yFYIwLdNL8-PUT3K3DpL11ob1Yrn10Jrc3bqH01_ZDcjHUO5YNWmJ7rWqdWe_by1DS-mV7pbTzrqhit8-gRLCF71bJKuPCvFXBtG993Kt9tCvvtCq1P2uORuWzPX-op83nq8tPsxtw-_763eziFmja0QJGhvmoDUFUaCMG1XM0QNZr0_cd0wPEA8bIEKawRp3SVPBRccNHjEbIKGbktHmz011Nw9Iabat35eUquaVKaxmVk38jwX2R8_hdMtZ1mJMq8OJBIMVvk81FLl3WdU8VbJyyRD2hWHRC0Ep9_g91EacU6nqVVeUY4XDjCO9YOsWckx33ZhCUm3zlLl9Z85XbfOV9HXp2uMZ-5E-alUB2hFyhMLfp4O__y_4GBJKyiA</recordid><startdate>20170830</startdate><enddate>20170830</enddate><creator>Aulić, Suzana</creator><creator>Masperone, Lara</creator><creator>Narkiewicz, Joanna</creator><creator>Isopi, Elisa</creator><creator>Bistaffa, Edoardo</creator><creator>Ambrosetti, Elena</creator><creator>Pastore, Beatrice</creator><creator>De Cecco, Elena</creator><creator>Scaini, Denis</creator><creator>Zago, Paola</creator><creator>Moda, Fabio</creator><creator>Tagliavini, Fabrizio</creator><creator>Legname, Giuseppe</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0716-4393</orcidid></search><sort><creationdate>20170830</creationdate><title>α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication</title><author>Aulić, Suzana ; Masperone, Lara ; Narkiewicz, Joanna ; Isopi, Elisa ; Bistaffa, Edoardo ; Ambrosetti, Elena ; Pastore, Beatrice ; De Cecco, Elena ; Scaini, Denis ; Zago, Paola ; Moda, Fabio ; Tagliavini, Fabrizio ; Legname, Giuseppe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-f526fcd3148cd8ba961b059cd9975cb02b221d35a2c17ac486fa6d6f21f054253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13/1</topic><topic>14</topic><topic>14/19</topic><topic>631/337/470/2284</topic><topic>631/378/1689/364</topic><topic>82/103</topic><topic>82/83</topic><topic>alpha-Synuclein - genetics</topic><topic>alpha-Synuclein - metabolism</topic><topic>Amyloid</topic><topic>Amyloid - administration & dosage</topic><topic>Amyloid - genetics</topic><topic>Amyloid - metabolism</topic><topic>Animals</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell spreading</topic><topic>Creutzfeldt-Jakob disease</topic><topic>Creutzfeldt-Jakob Syndrome - genetics</topic><topic>Creutzfeldt-Jakob Syndrome - metabolism</topic><topic>Creutzfeldt-Jakob Syndrome - pathology</topic><topic>Endopeptidase K - chemistry</topic><topic>Fibrils</topic><topic>Gene Expression Regulation</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Injections, Intraventricular</topic><topic>Internalization</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>multidisciplinary</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Prion protein</topic><topic>Prion Proteins - genetics</topic><topic>Prion Proteins - metabolism</topic><topic>Protein Binding</topic><topic>Protein Transport</topic><topic>Recombinant Proteins - genetics</topic><topic>Recombinant Proteins - metabolism</topic><topic>Replication</topic><topic>Rodents</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Scrapie</topic><topic>Signal Transduction</topic><topic>Stereotaxic Techniques</topic><topic>Synuclein</topic><topic>Tyrosine 3-Monooxygenase - genetics</topic><topic>Tyrosine 3-Monooxygenase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aulić, Suzana</creatorcontrib><creatorcontrib>Masperone, Lara</creatorcontrib><creatorcontrib>Narkiewicz, Joanna</creatorcontrib><creatorcontrib>Isopi, Elisa</creatorcontrib><creatorcontrib>Bistaffa, Edoardo</creatorcontrib><creatorcontrib>Ambrosetti, Elena</creatorcontrib><creatorcontrib>Pastore, Beatrice</creatorcontrib><creatorcontrib>De Cecco, Elena</creatorcontrib><creatorcontrib>Scaini, Denis</creatorcontrib><creatorcontrib>Zago, Paola</creatorcontrib><creatorcontrib>Moda, Fabio</creatorcontrib><creatorcontrib>Tagliavini, Fabrizio</creatorcontrib><creatorcontrib>Legname, Giuseppe</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech 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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aulić, Suzana</au><au>Masperone, Lara</au><au>Narkiewicz, Joanna</au><au>Isopi, Elisa</au><au>Bistaffa, Edoardo</au><au>Ambrosetti, Elena</au><au>Pastore, Beatrice</au><au>De Cecco, Elena</au><au>Scaini, Denis</au><au>Zago, Paola</au><au>Moda, Fabio</au><au>Tagliavini, Fabrizio</au><au>Legname, Giuseppe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-08-30</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>10050</spage><epage>12</epage><pages>10050-12</pages><artnum>10050</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>The precise molecular mechanism of how misfolded α-synuclein (α-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrP
C
) in mediating the uptake and the spread of recombinant α-Syn amyloids. The
in vitro
data revealed that the presence of PrP
C
fosters the higher uptake of α-Syn amyloid fibrils, which was also confirmed
in vivo
in wild type (
Prnp
+/+
) compared to PrP knock-out (
Prnp
−/−
) mice. Additionally, the presence of α-Syn amyloids blocked the replication of scrapie prions (PrP
Sc
)
in vitro
and
ex vivo
, indicating a link between the two proteins. Indeed, whilst PrP
C
is mediating the internalization of α-Syn amyloids, PrP
Sc
is not able to replicate in their presence. This observation has pathological relevance, since several reported case studies show that the accumulation of α-Syn amyloid deposits in Creutzfeldt-Jakob disease patients is accompanied by a longer disease course.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28855681</pmid><doi>10.1038/s41598-017-10236-x</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-0716-4393</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Scientific reports, 2017-08, Vol.7 (1), p.10050-12, Article 10050 |
| issn | 2045-2322 2045-2322 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5577263 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Springer Nature OA Free Journals; Nature Free; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | 13/1 14 14/19 631/337/470/2284 631/378/1689/364 82/103 82/83 alpha-Synuclein - genetics alpha-Synuclein - metabolism Amyloid Amyloid - administration & dosage Amyloid - genetics Amyloid - metabolism Animals Brain - metabolism Brain - pathology Cell Line, Tumor Cell spreading Creutzfeldt-Jakob disease Creutzfeldt-Jakob Syndrome - genetics Creutzfeldt-Jakob Syndrome - metabolism Creutzfeldt-Jakob Syndrome - pathology Endopeptidase K - chemistry Fibrils Gene Expression Regulation Humanities and Social Sciences Humans Injections, Intraventricular Internalization Mice Mice, Knockout multidisciplinary Neurons - metabolism Neurons - pathology Prion protein Prion Proteins - genetics Prion Proteins - metabolism Protein Binding Protein Transport Recombinant Proteins - genetics Recombinant Proteins - metabolism Replication Rodents Science Science (multidisciplinary) Scrapie Signal Transduction Stereotaxic Techniques Synuclein Tyrosine 3-Monooxygenase - genetics Tyrosine 3-Monooxygenase - metabolism |
| title | α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication |
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