Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

Abstract

The physiological importance of the degradative processes in lysosomes is revealed by the existence of at least 40 distinct inherited diseases, the so-called lysosomal storage disorders. Most of these diseases are caused by a deficiency in a single lysosomal enzyme, or essential cofactor, and result in the lysosomal accumulation of one, or sometimes several, natural compounds. The most prevalent subgroup of the lysosomal storage disorders is formed by the sphingolipidoses, inherited disorders that are characterized by excessive accumulation of one or multiple (glyco)sphingolipids. The biology of glycosphingolipids has been extensively discussed in other contributions during this symposium. This review will therefore focus in depth on (type 1) Gaucher disease, a prototypical glycosphingolipidosis. The elucidation of the primary genetic defect, being a deficiency in the lysosomal glucocerebrosidase, is described. Characterization of glucocerebrosidase at protein and gene level has subsequently opened avenues for therapeutic intervention. The development of successful enzyme replacement therapy for type 1 Gaucher disease is discussed. Attention is also paid to the alternative approach of substrate modulation using orally administered inhibitors of glucosylceramide synthesis. Novel developments about the monitoring of age of onset, progression and correction of disease are described. The remaining challenges about pathophysiology of glycosphingolipidoses are discussed in view of further improvements in therapy for these debilitating disorders.

The Glucosylceramide Synthase InhibitorN-(5-Adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin Induces Sterol Regulatory Element-Binding Protein-Regulated Gene Expression and Cholesterol Synthesis in HepG2 Cells

“…We have described previously that N-(5-adamantane-1-ylmethoxy-pentyl)-deoxynojirimycin (AMP-DNM), an inhibitor of glucosylceramide synthase, specifically lowers glycosphingolipid levels without affecting ceramide levels in various cell models (Overkleeft et al, 1998;Aerts et al, 2003;Wennekes et al, 2007). AMP-DNM was found to reverse insulin resistance and normalize blood glucose levels in animal models of diabetes and obesity (Zucker fa/fa rats, diet-induced obese mice, and ob/ob mice).…”

The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma

“…These microdomains provide conformational support for membrane proteins and contribute to the formation of plasma membrane signalosomes (50). The importance of sphingolipid homeostasis in human diseases was established by discoveries demonstrating the accumulation of glucosylceramide in Gaucher's disease (51) and in the pathogenesis of Alzheimer's disease (52). The sphingolipid biosynthesis pathway has been reviewed extensively (53,54).…”

N-Azidoacetylmannosamine-mediated chemical tagging of gangliosides

“…We also observed by flow cytometry analysis that after 3 days of culture of Jurkat cells in the presence of 10 mM AMP-DNM, cell surface ganglioside GM3 is reduced by 80% (data not shown). AMP-DNM is known not to interfere with glycoprotein biosynthesis and processing (22).…”