Pathophysiology of Gaucher disease in a macrophage

Normally, GBA1 is transcribed into mRNA, which is subsequently exported from the nucleus to the endoplasmic reticulum where glucocerebrosidase is synthesized. Glucocerebrosidase binds to LIMP-2, which is essential for the regulation of glucocerebrosidase transport from the endoplasmic reticulum through the Golgi apparatus (where the glucocerebrosidase protein undergoes maturation) to the lysosomes. The binding occurs at a neutral pH, and dissociation takes place within the acidic lysosomal environment. In the lysosome, with the support of its essential co-factor saposin C, glucocerebrosidase catalyzes the hydrolysis of GlcCer into glucose and ceramide. Due to a GBA1 mutation in Gaucher disease, the mutant glucocerebrosidase produced is a target for endoplasmic reticulum-associated degradation and proteasomal breakdown. Mutant glucocerebrosidase is unable to reach the lysosome, causing accumulation of GlcCer within the lysosomal compartment. The upregulated levels of intracellular GlcCer promote the formation of toxic soluble alpha-synuclein assemblies, exacerbating a pathogenic cycle by impairing the maturation of lysosomes and inhibiting the activity of functional glucocerebrosidase. This impairment results in further GlcCer accumulation and augmented alpha-synuclein formation due to its hampered degradation, leading to the release of inflammatory cytokines. The enzyme, known as GBA2 (the so-called second glucocerebrosidase), transforms GlcSph (also known as lyso-GlcCer) into sphingosine, which subsequently undergoes phosphorylation, resulting in the production of sphingosine-1-phosphate. Enhanced inflammatory response, along with the associated pathophysiology, contributes to bone fragility, lowering the erythrocyte and platelet levels and reducing lung function, and may also lead to neurodegeneration. Black arrows represent reactions that proceed normally. Broken red arrows indicate the normal reactions that do not occur. Solid red arrows denote the harmful reactions that do take place.

Abbreviations: GD, Gaucher disease; GCase, glucocerebrosidase; LIMP-2, lysosomal integral membrane protein 2; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; GlcCer, glucosylceramide; α-Syn, α-synuclein; GBA2, β-glucocerebrosidase 2; S1P, sphingosine-1-phosphate; lyso-GlcCer, lyso-glucosylceramide.

(Source: Feng S, Rcheulishvili N, Jiang X, et al. A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach. Int J Biol Sci 2024;20[6]:2111-29. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)