Resistance of naturally secreted α-synuclein to proteolysis

Recent evidence suggests that specific extracellular alpha-synuclein (alpha-syn) strains are implicated in the progression of Parkinson's disease (PD) pathology. It is plausible that deregulation in the normal processing of secreted alpha-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 alpha-syn levels. We show, for the first time, that cell-secreted alpha-syn forms are resistant to direct proteolysis by kallikrein-related peptidase 6 (KLK6), an extracellular enzyme known to cleave recombinant alpha-syn. This differential susceptibility appears to be partially due to the association of secreted alpha-syn with lipids. We further provide evidence that secreted alpha-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 alpha-syn. Our results clearly suggest that physiological modifications affect the biochemical behavior of secreted alpha-syn and provide novel insights into mechanisms and potential targets for therapeutic interventions.