Oncotarget

Research Papers:

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

Georgios Pampalakis, Vasia-Samantha Sykioti, Methodios Ximerakis, Ioanna Stefanakou-Kalakou, Ronald Melki, Kostas Vekrellis and Georgia Sotiropoulou _

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Oncotarget. 2017; 8:14502-14515. https://doi.org/10.18632/oncotarget.13264

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Abstract

Georgios Pampalakis1, Vasia-Samantha Sykioti2, Methodios Ximerakis2, Ioanna Stefanakou-Kalakou1, Ronald Melki3, Kostas Vekrellis2, Georgia Sotiropoulou1,2

1Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Athens, Greece

2Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece

3Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Gif-Sur-Yvette, France

Correspondence to:

Georgia Sotiropoulou, email: [email protected]

Kostas Vekrellis, email: [email protected]

Keywords: KLK6, α-synuclein, degradomics, metalloproteases, in vitro substrates

Received: July 28, 2016     Accepted: October 28, 2016     Published: November 10, 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.


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