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Article Dans Une Revue Oncotarget Année : 2017

KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species

Résumé

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.

Dates et versions

hal-01405158 , version 1 (29-11-2016)

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Georgios Pampalakis, Vasia-Samantha Sykioti, Methodios Ximerakis, Ioanna Stefanakou-Kalakou, Ronald Melki, et al.. KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species. Oncotarget, 2017, 8, pp.14502-14515. ⟨10.18632/oncotarget.13264⟩. ⟨hal-01405158⟩
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