The Complicated Relationship between Gaucher Disease and Parkinsonism: Insights from a Rare Disease

Abstract

The discovery of a link between mutations in GBA1, encoding the lysosomal enzyme glucocerebrosidase, and the synucleinopathies directly resulted from the clinical recognition of patients with Gaucher disease with parkinsonism. Mutations in GBA1 are now the most common known genetic risk factor for several Lewy body disorders, and an inverse relationship exists between levels of glucocerebrosidase and oligomeric α-synuclein. While the underlying mechanisms are still debated, this complicated association is shedding light on the role of lysosomes in neurodegenerative disorders, demonstrating how insights from a rare disorder can direct research into the pathogenesis and therapy of seemingly unrelated common diseases.

Keywords: Gaucher disease; alpha-synuclein; autophagy; glucocerebrosidase; lysosome; parkinsonism.

Figure 1. The inverse relationship between α-synuclein and glucocerebrosidase

Multiple factors can impact the inverse relationship including those leading to too much α-syn or two little GCase.

Figure 2. Pathways that might contribute to the association between GD and PD

Wild-type GCase is produced in the ER, glycosylated in the Golgi and is translocated to the lysosome where it degrades its substrate, GlcCer. (1) Mutant GCase may undergo proteosomal breakdown, is not translocated to lysosomes. (1a) GlcCer accumulates in the lysosome, which subsequently may lead to α-syn aggregation; however, not all individuals carrying a mutation develop PD. (2) In PD, the oligomeric form of α-syn may suppress ER-Golgi trafficking of GCase which can result in reduced GCase activity. (3) α-syn is a substrate for a selective form of autophagy (chaperone mediated autophagy, CMA) and interacts with the cytosolic chaperone (HSC70), enabling its translocation to the lysosome with the help of Lamp2a, a receptor for CMA on the lysosomal membrane. It is not known whether GCase is a substrate for CMA or if CMA is affected in patients with PD and GD. (4) Macroautophagy could be affected. Accumulation of ubiquitinated proteins and p62 in the autophagosome inhibits fusion between the autophagosome and the lysosome, which augments the accumulation of autophagosomes in the cells. These eventually inhibit macroautophagy and impair lysosomal function. (5) Transcription factor EB (TFEB), a key regulator of lysosome biogenesis may play a role. Under normal conditions, mTOR interacts with TFEB on the surface of the lysosome, which leads to TFEB phosphorylation and cytosolic sequestration of this transcription factor. When autophagy is impaired or mTOR is inhibited, TFEB is no longer phosphorylated, which results in the dissociation of TFEB from the lysosome and its translocation to the nucleus. α-syn accumulation or lysosomal dysfunction could inhibit translocation of TFEB to the nucleus, leading to the accumulation of phosphorylated TFEB on the lysosome.