Exploring the link between glucocerebrosidase mutations and parkinsonism

Abstract

Clinical, genetic and pathological studies demonstrate that mutations in glucocerebrosidase (GBA), which encodes the lysosomal enzyme deficient in Gaucher disease (GD), are risk factors for Parkinson disease (PD) and related disorders. Some patients with GD and Gaucher carriers develop parkinsonism. Furthermore, subjects with PD have an increased frequency of GBA mutations. GBA-mutation carriers exhibit diverse parkinsonian phenotypes and have glucocerebrosidase-positive Lewy bodies. Although the mechanism for this association is unknown, we present several theories, including protein aggregation, prion transmission, lipid accumulation and impaired autophagy, mitophagy or trafficking. Each model has inherent limitations, and a second-hit mutation might be essential. Elucidation of the basis for this link will have important consequences for studying these diseases and should provide insights into lysosomal pathways and potential treatment strategies.

Figure 1. Putative models for α-syn turnover pathways that could be affected in Gaucher disease

When GBA is mutated, there is impaired localization of misfolded GCase to the lysosome (1). Instead misfolded GCase undergoes ERAD via the UPS pathway through parkin-mediated ubiquitination (2). Accumulation of natural parkin substrates in the ER could cause ER stress followed by eventual cell death (3). The impaired localization of mutant GCase to the lysosome causes the substrate GC, and eventually other glycolipids, to accumulate in the lysosome (1). α-syn is degraded in part via CMA; altered lipid metabolism might interfere with the CMA pathway, resulting in impaired breakdown of α-syn (4). Altered lipid metabolism and accumulation in lysosomes can affect the composition of lipid microdomains on other endosomal vesicular compartments, causing elevated α-syn levels and aggregates (5). This can occur through impaired breakdown via the UPS (6) or via the CMA pathway (4). Mutant GCase might then contribute to α-syn aggregation and subsequent Lewy body formation (7).

Figure 2. Impaired ERAD-mediated breakdown of GCase

Wild type GCase enzyme gets transported to the lysosomes. Mutant misfolded GCase enzyme undergoes parkin-mediated poly-ubiquitination and subsequent proteasome-mediated degradation. The presence of mutant GCase might cause build-up of other parkin substrates causing ER-stress and eventual apoptosis of the neurons.

Figure 3. A theoretical model for α-syn as a prion in GBA- associated parkinsonism

Gaucher macrophages, which are present in patients with GD and might be acquired in carriers by a second hit, contain large lipid-laden structures owing to deficient glycolipid metabolism. In a Gaucher cell, large amounts of exogenously-ingested or endogenous α-syn could aggregate and acquire the prion form in the presence of an abundance of lipids. In a small number of patients, cellular death or enhanced transfer via exosomes could cause these Gaucher cells to unload the prion form of α-syn into the extracellular environment near neurons. Adapted with permission from Ref. [70]