KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.
Identifieur interne : 001B57 ( Ncbi/Merge ); précédent : 001B56; suivant : 001B58KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.
Auteurs : Georgios Pampalakis [Grèce] ; Vasia-Samantha Sykioti [Grèce] ; Methodios Ximerakis [Grèce] ; Ioanna Stefanakou-Kalakou [Grèce] ; Ronald Melki [France] ; Kostas Vekrellis [Grèce] ; Georgia Sotiropoulou [Grèce]Source :
- Oncotarget [ 1949-2553 ] ; 2016.
Abstract
KLK6 is a serine protease highly expressed in the nervous system. In synucleinopathies, including Parkinson disease, the levels of KLK6 inversely correlate with α-synuclein in CSF. Recently, we suggested that recombinant KLK6 mediates the degradation of extracellular α-synuclein directly and via a proteolytic cascade that involves unidentified metalloproteinase(s). Here, we show that recombinant and naturally secreted KLK6 can readily cleave α-synuclein fibrils that have the potential for cell-to-cell propagation in "a prion-like mechanism". Importantly, KLK6-deficient primary cortical neurons have increased ability for α-synuclein fibril uptake. We also demonstrate that KLK6 activates proMMP2, which in turn can cleave α-synuclein. The repertoire of proteases activated by KLK6 in a neuronal environment was analyzed by degradomic profiling, which also identified ADAMTS19 and showed that KLK6 has a limited number of substrates indicating specific biological functions such as the regulation of α-synuclein turnover. We generated adenoviral vectors for KLK6 delivery and demonstrated that the levels of extracellular α-synuclein can be reduced by neuronally secreted KLK6. Our findings open the possibility to exploit KLK6 as a novel therapeutic target for Parkinson disease and other synucleinopathies.
DOI: 10.18632/oncotarget.13264
PubMed: 27845893
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000059
- to stream PubMed, to step Curation: 000059
- to stream PubMed, to step Checkpoint: 000059
Links to Exploration step
pubmed:27845893Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.</title>
<author><name sortKey="Pampalakis, Georgios" sort="Pampalakis, Georgios" uniqKey="Pampalakis G" first="Georgios" last="Pampalakis">Georgios Pampalakis</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Sykioti, Vasia Samantha" sort="Sykioti, Vasia Samantha" uniqKey="Sykioti V" first="Vasia-Samantha" last="Sykioti">Vasia-Samantha Sykioti</name>
<affiliation wicri:level="1"><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ximerakis, Methodios" sort="Ximerakis, Methodios" uniqKey="Ximerakis M" first="Methodios" last="Ximerakis">Methodios Ximerakis</name>
<affiliation wicri:level="1"><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Stefanakou Kalakou, Ioanna" sort="Stefanakou Kalakou, Ioanna" uniqKey="Stefanakou Kalakou I" first="Ioanna" last="Stefanakou-Kalakou">Ioanna Stefanakou-Kalakou</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name>
<affiliation wicri:level="3"><nlm:affiliation>Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Gif-Sur-Yvette, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Gif-Sur-Yvette</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Gif-sur-Yvette</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Vekrellis, Kostas" sort="Vekrellis, Kostas" uniqKey="Vekrellis K" first="Kostas" last="Vekrellis">Kostas Vekrellis</name>
<affiliation wicri:level="1"><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Sotiropoulou, Georgia" sort="Sotiropoulou, Georgia" uniqKey="Sotiropoulou G" first="Georgia" last="Sotiropoulou">Georgia Sotiropoulou</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2016">2016</date>
<idno type="RBID">pubmed:27845893</idno>
<idno type="pmid">27845893</idno>
<idno type="doi">10.18632/oncotarget.13264</idno>
<idno type="wicri:Area/PubMed/Corpus">000059</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000059</idno>
<idno type="wicri:Area/PubMed/Curation">000059</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000059</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000059</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000059</idno>
<idno type="wicri:Area/Ncbi/Merge">001B57</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.</title>
<author><name sortKey="Pampalakis, Georgios" sort="Pampalakis, Georgios" uniqKey="Pampalakis G" first="Georgios" last="Pampalakis">Georgios Pampalakis</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Sykioti, Vasia Samantha" sort="Sykioti, Vasia Samantha" uniqKey="Sykioti V" first="Vasia-Samantha" last="Sykioti">Vasia-Samantha Sykioti</name>
<affiliation wicri:level="1"><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ximerakis, Methodios" sort="Ximerakis, Methodios" uniqKey="Ximerakis M" first="Methodios" last="Ximerakis">Methodios Ximerakis</name>
<affiliation wicri:level="1"><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Stefanakou Kalakou, Ioanna" sort="Stefanakou Kalakou, Ioanna" uniqKey="Stefanakou Kalakou I" first="Ioanna" last="Stefanakou-Kalakou">Ioanna Stefanakou-Kalakou</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name>
<affiliation wicri:level="3"><nlm:affiliation>Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Gif-Sur-Yvette, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Gif-Sur-Yvette</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Gif-sur-Yvette</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Vekrellis, Kostas" sort="Vekrellis, Kostas" uniqKey="Vekrellis K" first="Kostas" last="Vekrellis">Kostas Vekrellis</name>
<affiliation wicri:level="1"><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Sotiropoulou, Georgia" sort="Sotiropoulou, Georgia" uniqKey="Sotiropoulou G" first="Georgia" last="Sotiropoulou">Georgia Sotiropoulou</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation>
<country xml:lang="fr">Grèce</country>
<wicri:regionArea>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens</wicri:regionArea>
<wicri:noRegion>Athens</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Oncotarget</title>
<idno type="eISSN">1949-2553</idno>
<imprint><date when="2016" type="published">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">KLK6 is a serine protease highly expressed in the nervous system. In synucleinopathies, including Parkinson disease, the levels of KLK6 inversely correlate with α-synuclein in CSF. Recently, we suggested that recombinant KLK6 mediates the degradation of extracellular α-synuclein directly and via a proteolytic cascade that involves unidentified metalloproteinase(s). Here, we show that recombinant and naturally secreted KLK6 can readily cleave α-synuclein fibrils that have the potential for cell-to-cell propagation in "a prion-like mechanism". Importantly, KLK6-deficient primary cortical neurons have increased ability for α-synuclein fibril uptake. We also demonstrate that KLK6 activates proMMP2, which in turn can cleave α-synuclein. The repertoire of proteases activated by KLK6 in a neuronal environment was analyzed by degradomic profiling, which also identified ADAMTS19 and showed that KLK6 has a limited number of substrates indicating specific biological functions such as the regulation of α-synuclein turnover. We generated adenoviral vectors for KLK6 delivery and demonstrated that the levels of extracellular α-synuclein can be reduced by neuronally secreted KLK6. Our findings open the possibility to exploit KLK6 as a novel therapeutic target for Parkinson disease and other synucleinopathies.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">27845893</PMID>
<DateCreated><Year>2016</Year>
<Month>11</Month>
<Day>15</Day>
</DateCreated>
<DateRevised><Year>2016</Year>
<Month>11</Month>
<Day>16</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1949-2553</ISSN>
<JournalIssue CitedMedium="Internet"><PubDate><Year>2016</Year>
<Month>Nov</Month>
<Day>10</Day>
</PubDate>
</JournalIssue>
<Title>Oncotarget</Title>
<ISOAbbreviation>Oncotarget</ISOAbbreviation>
</Journal>
<ArticleTitle>KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.</ArticleTitle>
<ELocationID EIdType="doi" ValidYN="Y">10.18632/oncotarget.13264</ELocationID>
<Abstract><AbstractText NlmCategory="UNASSIGNED">KLK6 is a serine protease highly expressed in the nervous system. In synucleinopathies, including Parkinson disease, the levels of KLK6 inversely correlate with α-synuclein in CSF. Recently, we suggested that recombinant KLK6 mediates the degradation of extracellular α-synuclein directly and via a proteolytic cascade that involves unidentified metalloproteinase(s). Here, we show that recombinant and naturally secreted KLK6 can readily cleave α-synuclein fibrils that have the potential for cell-to-cell propagation in "a prion-like mechanism". Importantly, KLK6-deficient primary cortical neurons have increased ability for α-synuclein fibril uptake. We also demonstrate that KLK6 activates proMMP2, which in turn can cleave α-synuclein. The repertoire of proteases activated by KLK6 in a neuronal environment was analyzed by degradomic profiling, which also identified ADAMTS19 and showed that KLK6 has a limited number of substrates indicating specific biological functions such as the regulation of α-synuclein turnover. We generated adenoviral vectors for KLK6 delivery and demonstrated that the levels of extracellular α-synuclein can be reduced by neuronally secreted KLK6. Our findings open the possibility to exploit KLK6 as a novel therapeutic target for Parkinson disease and other synucleinopathies.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pampalakis</LastName>
<ForeName>Georgios</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sykioti</LastName>
<ForeName>Vasia-Samantha</ForeName>
<Initials>VS</Initials>
<AffiliationInfo><Affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ximerakis</LastName>
<ForeName>Methodios</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Stefanakou-Kalakou</LastName>
<ForeName>Ioanna</ForeName>
<Initials>I</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Melki</LastName>
<ForeName>Ronald</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Gif-Sur-Yvette, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Vekrellis</LastName>
<ForeName>Kostas</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sotiropoulou</LastName>
<ForeName>Georgia</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="">Journal Article</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2016</Year>
<Month>11</Month>
<Day>10</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Oncotarget</MedlineTA>
<NlmUniqueID>101532965</NlmUniqueID>
<ISSNLinking>1949-2553</ISSNLinking>
</MedlineJournalInfo>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">KLK6</Keyword>
<Keyword MajorTopicYN="N">degradomics</Keyword>
<Keyword MajorTopicYN="N">in vitro substrates</Keyword>
<Keyword MajorTopicYN="N">metalloproteases</Keyword>
<Keyword MajorTopicYN="N">α-synuclein</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year>
<Month>07</Month>
<Day>28</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2016</Year>
<Month>10</Month>
<Day>28</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2016</Year>
<Month>11</Month>
<Day>16</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2016</Year>
<Month>11</Month>
<Day>16</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2016</Year>
<Month>11</Month>
<Day>16</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>aheadofprint</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">27845893</ArticleId>
<ArticleId IdType="pii">13264</ArticleId>
<ArticleId IdType="doi">10.18632/oncotarget.13264</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
<affiliations><list><country><li>France</li>
<li>Grèce</li>
</country>
<region><li>Île-de-France</li>
</region>
<settlement><li>Gif-sur-Yvette</li>
</settlement>
</list>
<tree><country name="Grèce"><noRegion><name sortKey="Pampalakis, Georgios" sort="Pampalakis, Georgios" uniqKey="Pampalakis G" first="Georgios" last="Pampalakis">Georgios Pampalakis</name>
</noRegion>
<name sortKey="Sotiropoulou, Georgia" sort="Sotiropoulou, Georgia" uniqKey="Sotiropoulou G" first="Georgia" last="Sotiropoulou">Georgia Sotiropoulou</name>
<name sortKey="Stefanakou Kalakou, Ioanna" sort="Stefanakou Kalakou, Ioanna" uniqKey="Stefanakou Kalakou I" first="Ioanna" last="Stefanakou-Kalakou">Ioanna Stefanakou-Kalakou</name>
<name sortKey="Sykioti, Vasia Samantha" sort="Sykioti, Vasia Samantha" uniqKey="Sykioti V" first="Vasia-Samantha" last="Sykioti">Vasia-Samantha Sykioti</name>
<name sortKey="Vekrellis, Kostas" sort="Vekrellis, Kostas" uniqKey="Vekrellis K" first="Kostas" last="Vekrellis">Kostas Vekrellis</name>
<name sortKey="Ximerakis, Methodios" sort="Ximerakis, Methodios" uniqKey="Ximerakis M" first="Methodios" last="Ximerakis">Methodios Ximerakis</name>
</country>
<country name="France"><region name="Île-de-France"><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name>
</region>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonFranceV1/Data/Ncbi/Merge
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001B57 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Ncbi/Merge/biblio.hfd -nk 001B57 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Sante |area= ParkinsonFranceV1 |flux= Ncbi |étape= Merge |type= RBID |clé= pubmed:27845893 |texte= KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Ncbi/Merge/RBID.i -Sk "pubmed:27845893" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Ncbi/Merge/biblio.hfd \ | NlmPubMed2Wicri -a ParkinsonFranceV1
This area was generated with Dilib version V0.6.29. |