Mimicking Lysosomal Degradation of α-Synuclein

Abstract

Pathological accumulation of α-synuclein (α-syn) is a feature of Parkinson's disease. This accumulation may be counteracted by mechanisms of protein degradation that involve the proteasome and lysosome. Specifically, the lysosomal protease, Cathepsin D (CatD), has been suggested to be the main enzyme involved in the degradation of α-syn in vivo. In vitro, only C-terminal truncated species are generated, arguing that other mechanisms are needed to fully explain α-syn degradation. Here, we show that N-terminally acetylated α-syn also generates C-terminal as well as N-terminal truncated variants in the presence of CatD. These species are shown to be more aggregation prone. Since α-syn associates with membranes, we have investigated the effects of various glycosphingolipids such as glucosylceramide (GlcCer), on CatD degradation of α-syn. It is known that GlcCer buildup is a hallmark of the lysosomal storage disorder Gaucher disease and that these patients have an increased risk of developing PD. Our data clearly shows that in the presence of GlcCer and CatD, α-syn is completely proteolyzed. These data offer new mechanistic insight into α-syn degradation in the lysosome.