Glucocerebrosidase and parkinsonism: lessons to learn

Abstract

Both homo- (causing autosomal-recessive Gaucherʼs disease; GD) and heterozygous mutations in the glucocerebrosidase gene (GBA) are associated with Parkinson’s disease (PD), and represent the most robust known genetic susceptibility factors identified in PD. Since the accumulation of α-synuclein has been considered critical to the pathogenesis of PD among several possible pathways through which glucocerebrosidase (GCase) deficiency may promote the pathogenesis of PD, particular attention was given to the reciprocity with α-synuclein levels, lysosomal dysfunction, endoplasmatic reticulum–Golgi trafficking of GCase, dysregulation of calcium homeostasis and mitochondrial abnormalities. The proportion of PD patients that carry GBA mutations is estimated to be approximately between 5 and 10 %. Individual PD patients with or without GBA mutations cannot be discriminated on clinical or pathological grounds. However, GBA mutation carriers may have slightly earlier age at PD onset, more likely have a positive family history for PD, and more prevalent non-motor symptoms when compared to those patients who are not carriers. Establishing the concept of GBA-related PD promoted a search for the pathogenic mechanisms through which GCase deficiency may influence pathogenesis of PD, suggesting that targeting the GCase–lysosomal pathway might be a rational approach for the development of neuroprotective drugs in PD. © 2016, Springer-Verlag Berlin Heidelberg.