German research group discovers participation of a second enzyme
Jan. 8, 2013 — Accumulation of lipids in a cell can be life threatening. Lipid storage disorders are a group of inherited metabolic disorders. One of the most common storage disorders is the Gaucher disease. Patients with Gaucher disease suffer from severe enlargement of the liver and spleen. In the most severe cases, patients die at a young age.
The non-lysosomal beta-glucosidase GBA2 is a non-integral membrane-associated protein at the ER and Golgi
Background: The beta-glucosidase GBA2 degrades glucosylceramide (GlcCer) outside the lysosomes.
Results: GBA2 is not an integral membrane protein, but rather membrane-associated at the ER and Golgi.
Conclusion: GBA2 is located in a key position for a lysosomal-independent route of GlcCer-dependent signalling.
Significance: Understanding the localisation and activity of GBA2 is crucial for investigating the role of non-lysosomal glucosylceramide in Gaucher disease pathology.
It has been known for a while that the majority of patients with Gaucher disease carry mutations in a gene encoding for an enzyme called GBA1, which is responsible for the breakdown of a lipid called glucosylceramide. In those patients, GBA1 activity is severely reduced if not absent. Thus, Gaucher patients with a mutated Gba1 gene accumulate glucosylceramide, predominantly in spleen and liver.
As reported in a study published in Press in The Journal of Biological Chemistry, group from the Center of Advanced European Studies and Research (caesar) in Bonn, Germany, has shown now that the activity of a second β-glucosidase, GBA2, is also affected in Gaucher disease patients and might, thereby, regulate Gaucher disease progression. So far, GBA2 has been mainly attributed to male infertility: removal of the Gba2 gene in mice leads to a fertility defect due to the formation of abnormal sperm.
The scientists developed an assay that allows distinguishing between the activity of GBA1 and GBA2 in cells or tissues. Employing this novel assay, they demonstrated that GBA2 activity was dramatically reduced in skin cells from a Gaucher disease patient. The study describes a new role for GBA2 and puts the enzyme in a key position for lipid metabolism.