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- Title
Resistance of naturally secreted α-synuclein to proteolysis.
- Authors
Ximerakis, Methodios; Pampalakis, Georgios; Roumeliotis, Theodoros I.; Sykioti, Vasia-Samantha; Garbis, Spiros D.; Stefanis, Leonidas; Sotiropoulou, Georgia; Vekrellis, Kostas
- Abstract
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.
- Subjects
CYTOLOGICAL research; ENZYMES; LIPIDS; METABOLISM
- Publication
FASEB Journal, 2014, Vol 28, Issue 7, p3146
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.13-245852