Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease

Mutations in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson disease (PD). Homozygous or compound heterozygousGBA1mutations cause the lysosomal storage disorder Gaucher disease (GD), characterized by deficient activity of the glucocerebrosidase enzyme (GCase). Both individuals with GD type I and heterozygous carriers of pathogenic variants ofGBA1have an increased risk of developing PD, by approximately ten- to 20-fold compared to non-carriers. GCase activity is also reduced in PD patients withoutGBA1mutations, suggesting that the GCase lysosomal pathway might be involved in PD pathogenesis. Available evidence indicates that GCase can affect alpha-synuclein pathology in different ways. Misfolded GCase proteins are retained in the endoplasmic reticulum, altering the lysosomal trafficking of the enzyme and disrupting protein trafficking. Also, deficient GCase leads to accumulation of substrates that in turn may bind alpha-synuclein and promote pathological formation of aggregates. Furthermore, alpha-synuclein itself can lower the enzymatic activity of GCase, indicating that a bidirectional interaction exists between GCase and alpha-synuclein. Targeted therapies aimed at enhancing GCase activity, augmenting the trafficking of misfolded GCase proteins by small molecule chaperones, or reducing substrate accumulation, have been tested in preclinical and clinical trials. This article reviews the molecular mechanisms linking GCase to alpha-synuclein and discusses the therapeutic drugs that by targeting the GCase pathway can influence PD progression.