The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process
Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by the presence of proteinaceous aggregates of αSynuclein (αSyn) in the dopaminergic neurons. Chaperones are key components of the proteostasis network that are able to counteract αSyn's aggregation, as well...
Gespeichert in:
| Veröffentlicht in: | International journal of molecular sciences 2020-09, Vol.21 (19), p.7181 |
|---|---|
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 19 |
| container_start_page | 7181 |
| container_title | International journal of molecular sciences |
| container_volume | 21 |
| creator | Lenzi, Chiara Ramazzina, Ileana Russo, Isabella Filippini, Alice Bettuzzi, Saverio Rizzi, Federica |
| description | Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by the presence of proteinaceous aggregates of αSynuclein (αSyn) in the dopaminergic neurons. Chaperones are key components of the proteostasis network that are able to counteract αSyn's aggregation, as well as its toxic effects. Clusterin (CLU), a molecular chaperone, was consistently found to interfere with Aβ aggregation in Alzheimer's Disease (AD). However, its role in PD pathogenesis has yet to be extensively investigated. In this study, we assessed the involvement of CLU in the αSyn aggregation process by using SH-SY5Y cells stably overexpressing αSyn (SH-Syn). First, we showed that αSyn overexpression caused a strong increase in CLU expression without affecting levels of Hsp27, Hsp70, and Hsp90, which are the chaperones widely recognized to counteract αSyn burden. Then, we demonstrated that αSyn aggregation, induced by proteasome inhibition, determines a strong increase of CLU in insoluble aggregates. Remarkably, we revealed that CLU down-regulation results in an increase of αSyn aggregates in SH-Syn without significantly affecting cell viability and the Unfolded Protein Response (UPR). Furthermore, we demonstrated the direct molecular interaction between CLU and αSyn via a co-immunoprecipitation (co-IP) assay. All together, these findings provide incontrovertible evidence that CLU is an important player in the response orchestrated by the cell to cope with αSyn burden. |
| doi_str_mv | 10.3390/ijms21197181 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7582711</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2548671611</sourcerecordid><originalsourceid>FETCH-LOGICAL-c412t-41e32a91a158b375f4e86476dd1ae27c3e5ed1d541dcc0a53b4ac521708556093</originalsourceid><addsrcrecordid>eNpVkdtOwzAMhiME4nzHNarELYU4aZr2BgmNcZAmgWBI3EVZ6nWdumQkLYfH4kV4JjoGaFzZsj___mUTcgD0hPOcnlbTWWAAuYQM1sg2JIzFlKZyfSXfIjshTCllnIl8k2xxTinnLNsmT8MJRhfu1cb3WLa1bipnIzeOenUbGvSVjfpvc48hLOp9O9HWYIiabujz4-HdtqbGjjkvS4_lcvjOuw4Je2RjrOuA-z9xlzxe9oe963hwe3XTOx_EJgHWxAkgZzoHDSIbcSnGCWZpItOiAI1MGo4CCyhEAoUxVAs-SrQRDCTNhEhpznfJ2VJ33o5mWBi0jde1mvtqpv27crpS_zu2mqjSvSgpMiYBOoGjHwHvnlsMjZq61tvOs2IiyVIJ6Td1vKSMdyF4HP9tAKoWf1Crf-jww1VXf_Dv4fkXYyWFjg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2548671611</pqid></control><display><type>article</type><title>The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process</title><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Lenzi, Chiara ; Ramazzina, Ileana ; Russo, Isabella ; Filippini, Alice ; Bettuzzi, Saverio ; Rizzi, Federica</creator><creatorcontrib>Lenzi, Chiara ; Ramazzina, Ileana ; Russo, Isabella ; Filippini, Alice ; Bettuzzi, Saverio ; Rizzi, Federica</creatorcontrib><description>Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by the presence of proteinaceous aggregates of αSynuclein (αSyn) in the dopaminergic neurons. Chaperones are key components of the proteostasis network that are able to counteract αSyn's aggregation, as well as its toxic effects. Clusterin (CLU), a molecular chaperone, was consistently found to interfere with Aβ aggregation in Alzheimer's Disease (AD). However, its role in PD pathogenesis has yet to be extensively investigated. In this study, we assessed the involvement of CLU in the αSyn aggregation process by using SH-SY5Y cells stably overexpressing αSyn (SH-Syn). First, we showed that αSyn overexpression caused a strong increase in CLU expression without affecting levels of Hsp27, Hsp70, and Hsp90, which are the chaperones widely recognized to counteract αSyn burden. Then, we demonstrated that αSyn aggregation, induced by proteasome inhibition, determines a strong increase of CLU in insoluble aggregates. Remarkably, we revealed that CLU down-regulation results in an increase of αSyn aggregates in SH-Syn without significantly affecting cell viability and the Unfolded Protein Response (UPR). Furthermore, we demonstrated the direct molecular interaction between CLU and αSyn via a co-immunoprecipitation (co-IP) assay. All together, these findings provide incontrovertible evidence that CLU is an important player in the response orchestrated by the cell to cope with αSyn burden.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21197181</identifier><identifier>PMID: 33003328</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Aggregates ; alpha-Synuclein - genetics ; Alzheimer's disease ; Amyloid beta-Peptides - genetics ; Brain research ; Cell viability ; Chaperones ; Clusterin ; Clusterin - genetics ; Dopamine receptors ; Dopaminergic Neurons - metabolism ; Dopaminergic Neurons - pathology ; Gene Expression Regulation - genetics ; Heat shock proteins ; Heat-Shock Proteins - genetics ; Hsp27 protein ; HSP70 Heat-Shock Proteins - genetics ; Hsp70 protein ; HSP90 Heat-Shock Proteins - genetics ; Hsp90 protein ; Humans ; Immunoprecipitation ; Molecular Chaperones - genetics ; Molecular interactions ; Molecular weight ; Neuroblastoma ; Parkinson Disease - genetics ; Parkinson Disease - pathology ; Parkinson's disease ; Pathogenesis ; Proteasomes ; Protein Aggregation, Pathological - genetics ; Protein Aggregation, Pathological - pathology ; Protein folding ; Unfolded Protein Response - genetics</subject><ispartof>International journal of molecular sciences, 2020-09, Vol.21 (19), p.7181</ispartof><rights>2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-41e32a91a158b375f4e86476dd1ae27c3e5ed1d541dcc0a53b4ac521708556093</citedby><cites>FETCH-LOGICAL-c412t-41e32a91a158b375f4e86476dd1ae27c3e5ed1d541dcc0a53b4ac521708556093</cites><orcidid>0000-0003-1009-2917 ; 0000-0001-6271-148X</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/PMC7582711/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582711/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33003328$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lenzi, Chiara</creatorcontrib><creatorcontrib>Ramazzina, Ileana</creatorcontrib><creatorcontrib>Russo, Isabella</creatorcontrib><creatorcontrib>Filippini, Alice</creatorcontrib><creatorcontrib>Bettuzzi, Saverio</creatorcontrib><creatorcontrib>Rizzi, Federica</creatorcontrib><title>The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by the presence of proteinaceous aggregates of αSynuclein (αSyn) in the dopaminergic neurons. Chaperones are key components of the proteostasis network that are able to counteract αSyn's aggregation, as well as its toxic effects. Clusterin (CLU), a molecular chaperone, was consistently found to interfere with Aβ aggregation in Alzheimer's Disease (AD). However, its role in PD pathogenesis has yet to be extensively investigated. In this study, we assessed the involvement of CLU in the αSyn aggregation process by using SH-SY5Y cells stably overexpressing αSyn (SH-Syn). First, we showed that αSyn overexpression caused a strong increase in CLU expression without affecting levels of Hsp27, Hsp70, and Hsp90, which are the chaperones widely recognized to counteract αSyn burden. Then, we demonstrated that αSyn aggregation, induced by proteasome inhibition, determines a strong increase of CLU in insoluble aggregates. Remarkably, we revealed that CLU down-regulation results in an increase of αSyn aggregates in SH-Syn without significantly affecting cell viability and the Unfolded Protein Response (UPR). Furthermore, we demonstrated the direct molecular interaction between CLU and αSyn via a co-immunoprecipitation (co-IP) assay. All together, these findings provide incontrovertible evidence that CLU is an important player in the response orchestrated by the cell to cope with αSyn burden.</description><subject>Aggregates</subject><subject>alpha-Synuclein - genetics</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - genetics</subject><subject>Brain research</subject><subject>Cell viability</subject><subject>Chaperones</subject><subject>Clusterin</subject><subject>Clusterin - genetics</subject><subject>Dopamine receptors</subject><subject>Dopaminergic Neurons - metabolism</subject><subject>Dopaminergic Neurons - pathology</subject><subject>Gene Expression Regulation - genetics</subject><subject>Heat shock proteins</subject><subject>Heat-Shock Proteins - genetics</subject><subject>Hsp27 protein</subject><subject>HSP70 Heat-Shock Proteins - genetics</subject><subject>Hsp70 protein</subject><subject>HSP90 Heat-Shock Proteins - genetics</subject><subject>Hsp90 protein</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Molecular Chaperones - genetics</subject><subject>Molecular interactions</subject><subject>Molecular weight</subject><subject>Neuroblastoma</subject><subject>Parkinson Disease - genetics</subject><subject>Parkinson Disease - pathology</subject><subject>Parkinson's disease</subject><subject>Pathogenesis</subject><subject>Proteasomes</subject><subject>Protein Aggregation, Pathological - genetics</subject><subject>Protein Aggregation, Pathological - pathology</subject><subject>Protein folding</subject><subject>Unfolded Protein Response - genetics</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpVkdtOwzAMhiME4nzHNarELYU4aZr2BgmNcZAmgWBI3EVZ6nWdumQkLYfH4kV4JjoGaFzZsj___mUTcgD0hPOcnlbTWWAAuYQM1sg2JIzFlKZyfSXfIjshTCllnIl8k2xxTinnLNsmT8MJRhfu1cb3WLa1bipnIzeOenUbGvSVjfpvc48hLOp9O9HWYIiabujz4-HdtqbGjjkvS4_lcvjOuw4Je2RjrOuA-z9xlzxe9oe963hwe3XTOx_EJgHWxAkgZzoHDSIbcSnGCWZpItOiAI1MGo4CCyhEAoUxVAs-SrQRDCTNhEhpznfJ2VJ33o5mWBi0jde1mvtqpv27crpS_zu2mqjSvSgpMiYBOoGjHwHvnlsMjZq61tvOs2IiyVIJ6Td1vKSMdyF4HP9tAKoWf1Crf-jww1VXf_Dv4fkXYyWFjg</recordid><startdate>20200929</startdate><enddate>20200929</enddate><creator>Lenzi, Chiara</creator><creator>Ramazzina, Ileana</creator><creator>Russo, Isabella</creator><creator>Filippini, Alice</creator><creator>Bettuzzi, Saverio</creator><creator>Rizzi, Federica</creator><general>MDPI AG</general><general>MDPI</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1009-2917</orcidid><orcidid>https://orcid.org/0000-0001-6271-148X</orcidid></search><sort><creationdate>20200929</creationdate><title>The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process</title><author>Lenzi, Chiara ; Ramazzina, Ileana ; Russo, Isabella ; Filippini, Alice ; Bettuzzi, Saverio ; Rizzi, Federica</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-41e32a91a158b375f4e86476dd1ae27c3e5ed1d541dcc0a53b4ac521708556093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aggregates</topic><topic>alpha-Synuclein - genetics</topic><topic>Alzheimer's disease</topic><topic>Amyloid beta-Peptides - genetics</topic><topic>Brain research</topic><topic>Cell viability</topic><topic>Chaperones</topic><topic>Clusterin</topic><topic>Clusterin - genetics</topic><topic>Dopamine receptors</topic><topic>Dopaminergic Neurons - metabolism</topic><topic>Dopaminergic Neurons - pathology</topic><topic>Gene Expression Regulation - genetics</topic><topic>Heat shock proteins</topic><topic>Heat-Shock Proteins - genetics</topic><topic>Hsp27 protein</topic><topic>HSP70 Heat-Shock Proteins - genetics</topic><topic>Hsp70 protein</topic><topic>HSP90 Heat-Shock Proteins - genetics</topic><topic>Hsp90 protein</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Molecular Chaperones - genetics</topic><topic>Molecular interactions</topic><topic>Molecular weight</topic><topic>Neuroblastoma</topic><topic>Parkinson Disease - genetics</topic><topic>Parkinson Disease - pathology</topic><topic>Parkinson's disease</topic><topic>Pathogenesis</topic><topic>Proteasomes</topic><topic>Protein Aggregation, Pathological - genetics</topic><topic>Protein Aggregation, Pathological - pathology</topic><topic>Protein folding</topic><topic>Unfolded Protein Response - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lenzi, Chiara</creatorcontrib><creatorcontrib>Ramazzina, Ileana</creatorcontrib><creatorcontrib>Russo, Isabella</creatorcontrib><creatorcontrib>Filippini, Alice</creatorcontrib><creatorcontrib>Bettuzzi, Saverio</creatorcontrib><creatorcontrib>Rizzi, Federica</creatorcontrib><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>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</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>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</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 China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lenzi, Chiara</au><au>Ramazzina, Ileana</au><au>Russo, Isabella</au><au>Filippini, Alice</au><au>Bettuzzi, Saverio</au><au>Rizzi, Federica</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2020-09-29</date><risdate>2020</risdate><volume>21</volume><issue>19</issue><spage>7181</spage><pages>7181-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by the presence of proteinaceous aggregates of αSynuclein (αSyn) in the dopaminergic neurons. Chaperones are key components of the proteostasis network that are able to counteract αSyn's aggregation, as well as its toxic effects. Clusterin (CLU), a molecular chaperone, was consistently found to interfere with Aβ aggregation in Alzheimer's Disease (AD). However, its role in PD pathogenesis has yet to be extensively investigated. In this study, we assessed the involvement of CLU in the αSyn aggregation process by using SH-SY5Y cells stably overexpressing αSyn (SH-Syn). First, we showed that αSyn overexpression caused a strong increase in CLU expression without affecting levels of Hsp27, Hsp70, and Hsp90, which are the chaperones widely recognized to counteract αSyn burden. Then, we demonstrated that αSyn aggregation, induced by proteasome inhibition, determines a strong increase of CLU in insoluble aggregates. Remarkably, we revealed that CLU down-regulation results in an increase of αSyn aggregates in SH-Syn without significantly affecting cell viability and the Unfolded Protein Response (UPR). Furthermore, we demonstrated the direct molecular interaction between CLU and αSyn via a co-immunoprecipitation (co-IP) assay. All together, these findings provide incontrovertible evidence that CLU is an important player in the response orchestrated by the cell to cope with αSyn burden.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33003328</pmid><doi>10.3390/ijms21197181</doi><orcidid>https://orcid.org/0000-0003-1009-2917</orcidid><orcidid>https://orcid.org/0000-0001-6271-148X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1422-0067 |
| ispartof | International journal of molecular sciences, 2020-09, Vol.21 (19), p.7181 |
| issn | 1422-0067 1661-6596 1422-0067 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7582711 |
| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Aggregates alpha-Synuclein - genetics Alzheimer's disease Amyloid beta-Peptides - genetics Brain research Cell viability Chaperones Clusterin Clusterin - genetics Dopamine receptors Dopaminergic Neurons - metabolism Dopaminergic Neurons - pathology Gene Expression Regulation - genetics Heat shock proteins Heat-Shock Proteins - genetics Hsp27 protein HSP70 Heat-Shock Proteins - genetics Hsp70 protein HSP90 Heat-Shock Proteins - genetics Hsp90 protein Humans Immunoprecipitation Molecular Chaperones - genetics Molecular interactions Molecular weight Neuroblastoma Parkinson Disease - genetics Parkinson Disease - pathology Parkinson's disease Pathogenesis Proteasomes Protein Aggregation, Pathological - genetics Protein Aggregation, Pathological - pathology Protein folding Unfolded Protein Response - genetics |
| title | The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T07%3A18%3A02IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20Down-Regulation%20of%20Clusterin%20Expression%20Enhances%20the%20%CE%B1Synuclein%20Aggregation%20Process&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Lenzi,%20Chiara&rft.date=2020-09-29&rft.volume=21&rft.issue=19&rft.spage=7181&rft.pages=7181-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms21197181&rft_dat=%3Cproquest_pubme%3E2548671611%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2548671611&rft_id=info:pmid/33003328&rfr_iscdi=true |