KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.
Identifieur interne : 000251 ( Main/Merge ); précédent : 000250; suivant : 000252KLK6 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.
Url:
DOI: 10.18632/oncotarget.13264
PubMed: 27845893
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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 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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 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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><double doi="10.18632/oncotarget.13264"><HAL><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"><hal:affiliation type="institution" xml:id="struct-474026" status="INCOMING"> <orgName>Department of Pharmacy, School of Health Sciences</orgName> <desc> <address> <addrLine>University of Patras, Rion-Patras, Athens</addrLine> <country key="GR"></country> </address> </desc></hal:affiliation><country>Grèce</country></affiliation></author><author><name sortKey="Sykioti, Vasia Samantha" sort="Sykioti, Vasia Samantha" uniqKey="Sykioti V" 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</desc></org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author><author><name sortKey="Vekrellis, Kostas" sort="Vekrellis, Kostas" uniqKey="Vekrellis K" first="Kostas" last="Vekrellis">Kostas Vekrellis</name><affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-474027" status="INCOMING"> <orgName>Center for Neurosciences, Biomedical Research Foundation</orgName> <desc> <address> <addrLine>Academy of Athens, Athens</addrLine> <country key="GR"></country> </address> </desc></hal:affiliation><country>Grèce</country></affiliation></author><author><name sortKey="Sotiropoulou, Georgia" sort="Sotiropoulou, Georgia" uniqKey="Sotiropoulou G" first="Georgia" last="Sotiropoulou">Georgia Sotiropoulou</name><affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-474026" status="INCOMING"> <orgName>Department of Pharmacy, School of Health Sciences</orgName> <desc> <address> <addrLine>University of Patras, Rion-Patras, Athens</addrLine> <country key="GR"></country> </address> </desc></hal:affiliation><country>Grèce</country></affiliation></author></analytic><idno type="DOI">10.18632/oncotarget.13264</idno><series><title level="j">Oncotarget</title><idno type="ISSN">1949-2553</idno><imprint><date type="datePub">2016-11-10</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></HAL><PubMed><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><idno type="wicri:Area/Ncbi/Curation">001B57</idno><idno type="wicri:Area/Ncbi/Checkpoint">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></double></record>Pour manipuler ce document sous Unix (Dilib)
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