Abstract
The GBA2 gene encodes the non-lysosomal glucosylceramidase (NLGase), an enzyme that catalyzes the conversion of glucosylceramide (GlcCer) to ceramide and glucose. Mutations in GBA2 have been associated with the development of neurological disorders such as autosomal recessive cerebellar ataxia, hereditary spastic paraplegia, and Marinesco-Sjogren-Like Syndrome. Our group has previously identified the GBA2 c.1780G>C [p.Asp594His] missense mutation, in a Cypriot consanguineous family with spastic ataxia. In this study, we carried out a biochemical characterization of lymphoblastoid cell lines (LCLs) derived from three patients of this family. We found that the mutation strongly reduce NLGase activity both intracellularly and at the plasma membrane level. Additionally, we observed a two-fold increase of GlcCer content in LCLs derived from patients compared to controls, with the C16 lipid being the most abundant GlcCer species. Moreover, we showed that there is an apparent compensatory effect between NLGase and the lysosomal glucosylceramidase (GCase), since we found that the activity of GCase was three-fold higher in LCLs derived from patients compared to controls. We conclude that the c.1780G>C mutation results in NLGase loss of function with abolishment of the enzymatic activity and accumulation of GlcCer accompanied by a compensatory increase in GCase.
Highlights
Sphingolipids (SLs) are a class of lipids mainly associated with the external leaflet of the plasma membrane (PM) of all eukaryotic cells, playing an important role in the structural integrity of the PM and cellular signaling [1]
GSL catabolism occurs by the sequential hydrolysis of the saccharidic chain by removing the reducing sugar
Lysosomes are involved in the catabolism of the endocytic portion of the cell PM and could be considered the principal site, together with the endoplasmic reticulum and Golgi complex, responsible for GSLs turnover [34]
Summary
Sphingolipids (SLs) are a class of lipids mainly associated with the external leaflet of the plasma membrane (PM) of all eukaryotic cells, playing an important role in the structural integrity of the PM and cellular signaling [1]. SLs play a fundamental role in cell physiology and this can be demonstrated by the numerous genetic diseases that arise from mutations in enzymes involved in SL metabolism and transport [3,4]. Cells can alter their lipid composition by the action of different hydrolases that are active at the lysosomes or at the PM, such as sphingomyelinase (SMase), β-hexosaminidase (β-Hex), β-galactosidase (β-gal), β-glucocerebrosidase (GCase), and the non-lysosomal β-glucosylceramidase (NLGase) [5,6]. Loss of function mutations in the GBA gene cause Gaucher disease, the most common lysosomal storage disorder [7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
