KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.
Identifieur interne : 000059 ( PubMed/Corpus ); précédent : 000058; suivant : 000060KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.
Auteurs : Georgios Pampalakis ; Vasia-Samantha Sykioti ; Methodios Ximerakis ; Ioanna Stefanakou-Kalakou ; Ronald Melki ; Kostas Vekrellis ; Georgia SotiropoulouSource :
- 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
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Ximerakis</name><affiliation><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation></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><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation></affiliation></author><author><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name><affiliation><nlm:affiliation>Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Gif-Sur-Yvette, France.</nlm:affiliation></affiliation></author><author><name sortKey="Vekrellis, Kostas" sort="Vekrellis, Kostas" uniqKey="Vekrellis K" first="Kostas" last="Vekrellis">Kostas Vekrellis</name><affiliation><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation></affiliation></author><author><name sortKey="Sotiropoulou, Georgia" sort="Sotiropoulou, Georgia" uniqKey="Sotiropoulou G" first="Georgia" last="Sotiropoulou">Georgia Sotiropoulou</name><affiliation><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation></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></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><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation></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><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation></affiliation></author><author><name sortKey="Ximerakis, Methodios" sort="Ximerakis, Methodios" uniqKey="Ximerakis M" first="Methodios" last="Ximerakis">Methodios Ximerakis</name><affiliation><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation></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><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation></affiliation></author><author><name sortKey="Melki, Ronald" sort="Melki, Ronald" uniqKey="Melki R" first="Ronald" last="Melki">Ronald Melki</name><affiliation><nlm:affiliation>Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Gif-Sur-Yvette, France.</nlm:affiliation></affiliation></author><author><name sortKey="Vekrellis, Kostas" sort="Vekrellis, Kostas" uniqKey="Vekrellis K" first="Kostas" last="Vekrellis">Kostas Vekrellis</name><affiliation><nlm:affiliation>Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.</nlm:affiliation></affiliation></author><author><name sortKey="Sotiropoulou, Georgia" sort="Sotiropoulou, Georgia" uniqKey="Sotiropoulou G" first="Georgia" last="Sotiropoulou">Georgia Sotiropoulou</name><affiliation><nlm:affiliation>Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece.</nlm:affiliation></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></record>Pour manipuler ce document sous Unix (Dilib)
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