Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece;
Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Greece;
FASEB J. 2014 Jul;28(7):3146-58. doi: 10.1096/fj.13-245852. Epub 2014 Apr 10.
Recent evidence suggests that specific extracellular α-synuclein (α-syn) strains are implicated in the progression of Parkinson's disease (PD) pathology. It is plausible that deregulation in the normal processing of secreted α-syn may be a causative risk factor for PD. To date, the degradation mechanisms involved have received very little attention. Here, we sought to investigate factors that regulate extracellular α-syn levels. We show, for the first time, that cell-secreted α-syn forms are resistant to direct proteolysis by kallikrein-related peptidase 6 (KLK6), an extracellular enzyme known to cleave recombinant α-syn. This differential susceptibility appears to be partially due to the association of secreted α-syn with lipids. We further provide evidence that secreted α-syn can be cleaved by KLK6 indirectly through activation of a secreted metalloprotease, suggestive of the involvement of a proteolytic cascade in the catabolism of secreted α-syn. Our results clearly suggest that physiological modifications affect the biochemical behavior of secreted α-syn and provide novel insights into mechanisms and potential targets for therapeutic interventions.-Ximerakis, M., Pampalakis, G., Roumeliotis, T. I., Sykioti, V.-S., Garbis, S. D., Stefanis, L., Sotiropoulou, G., Vekrellis, K. Resistance of naturally secreted α-synuclein to proteolysis.
最近的证据表明，特定的细胞外α-突触核蛋白（α-syn）菌株与帕金森病（PD）病理的进展有关。α-syn 的分泌过程失调可能是 PD 的一个致病风险因素，这是合理的。迄今为止，涉及的降解机制受到的关注很少。在这里，我们试图研究调节细胞外α-syn 水平的因素。我们首次表明，细胞分泌的α-syn 形式对激肽释放酶相关肽酶 6（KLK6）的直接蛋白水解具有抗性，KLK6 是一种已知可切割重组α-syn 的细胞外酶。这种差异敏感性似乎部分归因于分泌的α-syn 与脂质的结合。我们进一步提供证据表明，分泌的α-syn 可以通过激活分泌的金属蛋白酶间接被 KLK6 切割，提示分泌的α-syn 的代谢涉及蛋白水解级联。我们的研究结果清楚地表明，生理修饰会影响分泌的α-syn 的生化行为，并为治疗干预的机制和潜在靶点提供了新的见解。-Ximerakis，M.，Pampalakis，G.，Roumeliotis，T. I.，Sykioti，V.-S.，Garbis，S. D.，Stefanis，L.，Sotiropoulou，G.，Vekrellis，K. 天然分泌的 α-突触核蛋白对蛋白水解的抗性。
