Reply: Lysosomal dysfunction in Parkinson’s disease

Sir,McNeill highlights in his Letter to the Editor that glucocerebrosidase ( GBA ) gene mutation carriers have reduced glucosylceramidase protein and enzyme activity based on measurements obtained from patient fibroblasts (McNeill et al. , 2014). He links this to our data recently presented in Murphy et al. (2014) identifying similar findings in brain regions associated with increased α-synuclein early in Parkinson’s disease without GBA mutations, and suggests that reduced glucosylceramidase protein and enzyme activity plays a key early and not a secondary role in Parkinson’s disease. Although our data fully concur with this concept, we have been cautious to suggest an absolute direct link, i.e. reduced glucosylceramidase leads to increased α-synuclein, which leads to Parkinson’s disease, based on evidence that most carriers of GBA mutations (both with Gaucher disease and heterozygotes) do not develop Parkinson’s disease (Rana et al. , 2013; Alcalay et al. , 2014). Current data show that only 1–5% of patients with GBA mutations will have Parkinson’s disease by the age of …