KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.
Identifieur interne : 000249 ( Main/Exploration ); précédent : 000248; suivant : 000250KLK6 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
Affiliations:
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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><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)
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