Resistance of naturally secreted α-synuclein to proteolysis.
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.
Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece;
Methodios
M
Ximerakis
Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Greece;
Georgios
G
Pampalakis
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK; and.
Theodoros I
TI
Roumeliotis
Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece;
Vasia-Samantha
VS
Sykioti
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK; and.
Spiros D
SD
Garbis
Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece; Second Department of Neurology, University of Athens Medical School, Athens, Greece.
Leonidas
L
Stefanis
Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras, Greece;
Georgia
G
Sotiropoulou
Center for Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece; vekrellis@bioacademy.gr.
Kostas
K
Vekrellis
D002460:Cell Line; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism; D059748:Proteolysis; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein; D045726:Metalloproteases; C103551:KLK6 protein, human; D007610:Kallikreins
KLK6; Parkinson's disease; clearance; lipidation; metalloprotease