Defining a Molecular Link between Parkinson and Gaucher Diseases

National Heart, Lung, And Blood Institute

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Abstract

Mutations in the GBA1 gene are the most common of the known risk factors for Parkinson disease (PD). While clinical studies argue a strong case towards a link between GBA1 mutations and the development of PD, mechanistic insights have been lacking. GBA1 encodes glucocerebrosidase (GCase), a lysosomal enzyme which hydrolyzes glucosylceramide (GluCer) into glucose and ceramide and is deficient in Gaucher disease (GD). Recent research suggests a relationship between GCase and the PD-related amyloid-forming protein, alpha-synuclein (alpha-syn); however, the specific molecular mechanisms responsible for association remain elusive. In our work, we focused on the structure-function relationship of alpha-syn and GCase interaction in the lysosome. We have evaluated enzymatic activity, characterized the membrane-bound protein complex by neutron reflectometry, and assessed the effect of Saposin C, an activator for GCase, on complex formation and GCase activity. In defining the molecular interactions that drive the reciprocal relationship between GCase and alpha-syn levels in vivo, we have turned to investigate how alpha-syn is degraded in the lysosome. As the lysosome removes aggregation-prone species or excess levels of alpha-syn, molecular interactions that occur within the lysosome such as with GCase would be pertinent. Such interactions could modulate proteolysis efficiency by altering availability of alpha-syn cleavage sites and dictate protease specificity and efficacy. During this review period, we identified a highly potent lysosomal protease, cathepsin K (CtsK) that can completely disaggregate alpha-syn amyloid fibrils. We gained mechanistic insights into how this protease destabilizes the fibril structure by performing peptide mapping by liquid chromatography mass spectrometry which pinpointed critical cleavage sites that are central in destroying the amyloid core. Specifically, we showed that the disordered regions in the N- and C-termini play pivotal roles in protecting the fibril from protease degradation. Once these polypeptides are excised, rapid degradation of the amyloid core ensues. Furthermore, we demonstrate that CtsK is also capable of degrading fibrils formed by a PD-related mutant (A53T) and a LB-derived C-terminal truncation variant, both of which have enhanced aggregation propensity. We suggest a new strategy to ameliorate alpha-syn pathology by targeting lysosomes through gene therapy to enhance CtsK expression.