Figure 2.

GCase from birth to death. (a) Chromosome locus of GBA gene with 14 exons. More than 300 GBA variants are associated with GD and around 130 mutations are associated with PD [76]. (b) After GBA is transcribed into mRNA, it becomes synthesized in the ER and undergoes post-translational modifications, such as glycosylation [65]. The GCase enzyme attaches to LIMP2 and is guided to the Golgi and lysosomes. LIPM2 levels in SN of PD-GBA and iPD do not change [36], but levels are reduced in iPD fibroblasts and correlate with reduced GCase activity [63]. (c) After glycosylated-GCase reaches the lysosome it becomes activated by saposin C. (d) Activated GCase clears glucosylceramides engulfed inside the autophagosome; however, the incorrect conformational state of GCase and its deficient activity cause glucosylceramide accumulation in the lysosomes. (e) There seems to be a bidirectional effect between glucosylceramide accumulation and Lewy body formation. The presence of Lewy bodies is suggested to disrupt correct conformational states and trafficking of GCase proteins towards lysosomes [25] and vice versa, implicating the mutant GCase in αSyn aggregation [26,77]. (Created with BioRender.com. accessed on 22 December 2021).