Multi-system disorders of glycosphingolipid and ganglioside metabolism
2010; Elsevier BV; Volume: 51; Issue: 7 Linguagem: Inglês
10.1194/jlr.r003996
ISSN1539-7262
AutoresYongping Xu, Sonya Barnes, Ying Sun, Gregory A. Grabowski,
Tópico(s)Sphingolipid Metabolism and Signaling
ResumoGlycosphingolipids (GSLs) and gangliosides are a group of bioactive glycolipids that include cerebrosides, globosides, and gangliosides. These lipids play major roles in signal transduction, cell adhesion, modulating growth factor/hormone receptor, antigen recognition, and protein trafficking. Specific genetic defects in lysosomal hydrolases disrupt normal GSL and ganglioside metabolism leading to their excess accumulation in cellular compartments, particularly in the lysosome, i.e., lysosomal storage diseases (LSDs). The storage diseases of GSLs and gangliosides affect all organ systems, but the central nervous system (CNS) is primarily involved in many. Current treatments can attenuate the visceral disease, but the management of CNS involvement remains an unmet medical need. Early interventions that alter the CNS disease have shown promise in delaying neurologic involvement in several CNS LSDs. Consequently, effective treatment for such devastating inherited diseases requires an understanding of the early developmental and pathological mechanisms of GSL and ganglioside flux (synthesis and degradation) that underlie the CNS diseases. These are the focus of this review. Glycosphingolipids (GSLs) and gangliosides are a group of bioactive glycolipids that include cerebrosides, globosides, and gangliosides. These lipids play major roles in signal transduction, cell adhesion, modulating growth factor/hormone receptor, antigen recognition, and protein trafficking. Specific genetic defects in lysosomal hydrolases disrupt normal GSL and ganglioside metabolism leading to their excess accumulation in cellular compartments, particularly in the lysosome, i.e., lysosomal storage diseases (LSDs). The storage diseases of GSLs and gangliosides affect all organ systems, but the central nervous system (CNS) is primarily involved in many. Current treatments can attenuate the visceral disease, but the management of CNS involvement remains an unmet medical need. Early interventions that alter the CNS disease have shown promise in delaying neurologic involvement in several CNS LSDs. Consequently, effective treatment for such devastating inherited diseases requires an understanding of the early developmental and pathological mechanisms of GSL and ganglioside flux (synthesis and degradation) that underlie the CNS diseases. These are the focus of this review. Glycosphingolipids (GSLs) consist of ceramide and one or more attached carbohydrates. The nature of the oligosaccharide head groups categorizes the GSLs into neutral or acidic types due to the absence or presence of sialic acid residues, respectively (Fig. 1). Gangliosides are sialic acid containing GSLs. In eukaryotic cells, GSLs and gangliosides compose 10–20% of the total lipids (1.Holthuis J.C. Pomorski T. Raggers R.J. Sprong H. Van Meer G. The organizing potential of sphingolipids in intracellular membrane transport.Physiol. Rev. 2001; 81: 1689-1723Crossref PubMed Scopus (233) Google Scholar), which are important to a variety of cellular functions. GSLs and gangliosides are synthesized at the endoplasmic reticulum (ER) and are remodeled during transit from cis to trans Golgi by a series of glycosyl- and sialyl-transferases. These are then transported to the intracellular compartments and the plasma membrane where they become enriched in microdomains and membrane bilayers. During plasma membrane turnover, GSLs and gangliosides can be internalized and partially or completely degraded in the endosomal/lysosomal system to sphingosine and free fatty acids that are then transported or flipped across late endosomal and lysosomal membranes for recycling or for use as signaling molecules (2.Kolter T. Sandhoff K. 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Each of these saposins has specificity for a particular GSL hydrolase (Table 1).TABLE 1Human and mouse disorders of GSL and ganglioside degradationDisease (Frequencies)Gene Symbol, Chr. Location,aMouse Genome Database at the Mouse Genome Informatics Web site, The Jackson Laboratory, Bar Harbor, ME. World Wide Web (URL: http://www.informatics.jax.org), January, 2010. Name(s)SpeciesGene DefectbDetailed mutation information for each disease can be found in the references.Major Storage MaterialsPhenotypeOnsetLifespanReferencesFarber disease (lipo granulomatosis) (rare)ASAH1 Chr 8: p22-p21.3 AC, N-acylsphingosine amidohydrolase 1; N-acylsphingosine deacylase, AC, ASAH1Human>17 Different mutations including point mutations and splice-site mutationsCeramide, hydroxyl ceramideGranulomas, lipid-laden macrophages in the CNS and viscera, mild or no neurological involvement, subcutaneous skin nodules near or over joints0 days – 1.7 year3 days–16 year(96.Moser H. Linke T. Fensom A.H. Levade T. 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