The role of glycosphingolipids in health and disease forms the central research theme. Glycosphingolipids, a unique class of membrane lipids, reside largely at the cell surface with their glycans facing the external mileu. Glycsphingolipids interact with cholesterol to form transient semi-ordered microdomains in which selected proteins preferentially reside including some hormone receptors and GPI-anchored proteins. Glycosphingolipids are synthesized at the ER and Golgi apparatus and are degraded inside lysosomes. Impaired lysosomal degradation of glycosphingolipids forms the molecular basis of the so-called sphingolipidoses, a number of discrete lysosomal storage disorders (LSDs) including Gaucher, Fabry and Tay-Sachs disease. Biochemical aspects of LSDs have been investigated in close collaboration with national and international clinical colleagues (Prof.Dr. Hollak, AMC; Prof. Mistry. Yale; Prof. Cox, Cambridge). Dysregulation of glycosphingolipids is also associated with the metabolic syndrome and some neurodegenerative disorders. Abnormal concentrations of glycosphingolipids have been found to negatively effect cellular processes as well as the regulation of body metabolism.
The research group aims to study various aspects of glycosphingolipid metabolism and its impact by employing state-of-the art lipidomics, transcriptomics and proteomics. Systems biology is used to improve interpretation of complex data sets. Use is made for investigations of rodent models as well as materials obtained from patients and volunteers. Newly designed small-compounds in collaboration with Prof. Dr. Overkleeft and Prof. Dr. van der Marel (Organic Chemistry, Leiden University) are used to manipulate glycosphingolipid metabolism, as chaperones to stabilize mutant proteins and as tools to visualize specific hydrolases in vivo. The research group closely interacts with several national and international researchers, including the AMC, NIN, UMCU, LUMC, LIC-UL, Cambridge and Yale. Within the department MBIOC other research activities are associated with the the research group Aerts: Dr. Bleijlevens studying protein structure-function relationships, the unit for proteomics and lipidomics (Dr. Speijer). The fundamental research is assisted by an ERC Advanced Grant CHEMSPHING, jointly held with Prof. Overkleeft (LIC, UL). Recent highlights.
Novel methods for quantification of glycosphingolipids and new means for in vivo labeling of cell surface gangliosides were developed.
The role of sphingolipids in peripheral insulin resistance was elucidated. It was demonstrated that excessive formation of gangliosides occurs in obese animals and is associated with insulin resistance. Impaired glucose homeostasis in such animals is spectacularly corrected with patented iminosugar-type inhibitors of glycosphingolipid biosynthesis. Iminosugar treatment was also found to prevent other manifestations associated with the metabolic syndrome such as hepatosteatosis, atherosclerosis, hyperlipidemia and pancreatic beta-cell destruction.
Novel iminosugar modulators of glycosphingolipid metabolism were developed for the treatment of neuronopathic inherited lysosomal glycosphingolipid storage disorders. A hydrolase (GBA2) degrading glucosylceramide in the cytosol was further biochemically characterized and its pathological role in clinical manifestation of Gaucher disease and increased incidence of Parkinsonism among Gaucher carriers is studied. Novel metabolites, stemming from transglycosidase activity of glycosidases like GBA and GBA2, were discovered.The identification of novel metabolites opens new resarch avenues.
An improved assay with a novel substrate was developed for detection of the Gaucher plasma biomarker chitotriosidase (CHIT). Plasma CHIT is found to be also of interest in relation to atherosclerosis, various metabolic disorders, asthma and allergy. The evolution of the complex chitinase protein family in vertebrates was resolved and a relevant novel polymorphism in CHIT was detected. The biomarker potential of sphingoid bases such as glucosylsphingosine and globotriaosylsphingosine was substantiated. Accurate measurement of these and other sphingolipids using internal isotope-labeled standards and LC-MS/MS was developed. New proteomics approaches for quantitative biomarker discovery as well as disease pattern recognition were published.
A novel methodology was developed to visualize the hydrolase glucocerebrosidase (GBA) in vivo, employing fluorescent activity-based probes (suicide inhibitors).The so-called Inhibody approach is presently succesfully broadened to other glycosidases and their application in diagnosis and monitoring of diseases caused by (in)direct abnormaliies in cellular glycosidases is studied.. This research group participates in the AMC themes Metabolic Disorders and Cardiovascular Diseases.