| First Author | Pampalakis G | Year | 2017 |
| Journal | Oncotarget | Volume | 8 |
| Issue | 9 | Pages | 14502-14515 |
| PubMed ID | 27845893 | Mgi Jnum | J:290434 |
| Mgi Id | MGI:6441553 | Doi | 10.18632/oncotarget.13264 |
| Citation | Pampalakis G, et al. (2017) KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species. Oncotarget 8(9):14502-14515 |
| abstractText | KLK6 is a serine protease highly expressed in the nervous system. In synucleinopathies, including Parkinson disease, the levels of KLK6 inversely correlate with alpha-synuclein in CSF. Recently, we suggested that recombinant KLK6 mediates the degradation of extracellular alpha-synuclein directly and via a proteolytic cascade that involves unidentified metalloproteinase(s). Here, we show that recombinant and naturally secreted KLK6 can readily cleave alpha-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 alpha-synuclein fibril uptake. We also demonstrate that KLK6 activates proMMP2, which in turn can cleave alpha-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 alpha-synuclein turnover. We generated adenoviral vectors for KLK6 delivery and demonstrated that the levels of extracellular alpha-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. |
