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Resistance of naturally secreted α‐synuclein to proteolysis
Author(s) -
Ximerakis Methodios,
Pampalakis Georgios,
Roumeliotis Theodoros I.,
Sykioti VasiaSamantha,
Garbis Spiros D.,
Stefanis Leonidas,
Sotiropoulou Georgia,
Vekrellis Kostas
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-245852
Subject(s) - proteolysis , extracellular , secretion , secretory protein , metalloproteinase , biology , catabolism , microbiology and biotechnology , proteasome , biochemistry , enzyme , chemistry
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. FASEB J . 28, 3146–3158 (2014). www.fasebj.org