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

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

doi:10.18632/oncotarget.13264

Kostas Vekrellis, Georgia Sotiropoulou + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.13264

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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.

Highlights

The link between α-synuclein and Parkinson’s disease (PD) and other neurodegenerative diseases collectively called synucleinopathies is well documented [1]
Proteolytic processing of α-synuclein entails a metalloprotease, which must be activated by kallikrein-related peptidase 6 (KLK6)
Based on the ability of KLK6 to cleave α-synuclein and its decreased expression in patients, KLK6 was linked to PD and other synucleinopathies

Summary

Introduction

The link between α-synuclein and Parkinson’s disease (PD) and other neurodegenerative diseases collectively called synucleinopathies is well documented [1]. Emerging evidence suggests that extracellular α-synuclein may be implicated in the pathology of PD. According to a “prion-like” hypothesis, α-synuclein fibrils but not monomers can spread from one cell to another, to seed the intracellular α-synuclein monomers in a manner that resembles prion diseases, accelerating PD pathology [3, 4]. It is plausible that deregulation in the normal processing of secreted α-synuclein contributes to the formation of “toxic” α-synuclein species and fibrils and as such it may be a causative risk factor for PD. In this respect, proteolytic processing of extracellular α-synuclein emerges as a new important field for active investigation with potential implications for therapy

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