View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1758 (2006) 2057–2079 www.elsevier.com/locate/bbamem Review Sphingolipid metabolism diseases ⁎ Thomas Kolter, Konrad Sandhoff Kekulé-Institut für Organische Chemie und Biochemie der Universität, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany Received 23 December 2005; received in revised form 26 April 2006; accepted 23 May 2006 Available online 14 June 2006 Abstract Human diseases caused by alterations in the metabolism of sphingolipids or glycosphingolipids are mainly disorders of the degradation of these compounds. The sphingolipidoses are a group of monogenic inherited diseases caused by defects in the system of lysosomal sphingolipid degradation, with subsequent accumulation of non-degradable storage material in one or more organs. Most sphingolipidoses are associated with high mortality. Both, the ratio of substrate influx into the lysosomes and the reduced degradative capacity can be addressed by therapeutic approaches. In addition to symptomatic treatments, the current strategies for restoration of the reduced substrate degradation within the lysosome are enzyme replacement therapy (ERT), cell-mediated therapy (CMT) including bone marrow transplantation (BMT) and cell-mediated “cross correction”, gene therapy, and enzyme-enhancement therapy with chemical chaperones. The reduction of substrate influx into the lysosomes can be achieved by substrate reduction therapy. Patients suffering from the attenuated form (type 1) of Gaucher disease and from Fabry disease have been successfully treated with ERT. © 2006 Elsevier B.V. All rights reserved. Keywords: Ceramide; Lysosomal storage disease; Saposin; Sphingolipidose Contents 1. Sphingolipid structure, function and biosynthesis ..........................................2058 1.1. Less precisely defined is the role of sphingolipids in cancer [25]. ............................2058 1.2. Biosynthesis ..........................................................2058 2. Glycosphingolipid catabolism ....................................................2059 2.1. Topology ...........................................................2060 2.2. Sphingolipid activator proteins ................................................2060 2.3. Intralysosomal membranes ..................................................2060 3. Sphingolipidoses ...........................................................2062 3.1. GM1-gangliosidosis ......................................................2062 3.2. GM2-gangliosidoses ......................................................2063 3.3. Tay–Sachs disease.......................................................2063 3.4. Sandhoff disease........................................................2063 3.5. AB-variant of GM2-gangliosidosis ..............................................2064 3.6. Fabry disease .........................................................2064 3.7. Gaucher disease ........................................................2064 3.8. Metachromatic leukodystrophy ................................................2065 3.9. Krabbe disease ........................................................2066 3.10. Niemann–Pick disease, type A and B .............................................2067 3.11. Farber disease .........................................................2067 ⁎ Corresponding author. Tel.: +49 228 73 53 46; fax: +49 228 73 77 78. E-mail addresses: [email protected] (T. Kolter), [email protected] (K. Sandhoff). 0005-2736/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamem.2006.05.027 2058 T. Kolter, K. Sandhoff / Biochimica et Biophysica Acta 1758 (2006) 2057–2079 3.12. Deficiency of Saposins (Saps) ............................................... 2068 3.12.1. Prosaposin .................................................... 2068 3.12.2. Sap-A....................................................... 2068 3.12.3. Sap-B deficiency ................................................. 2068 3.12.4. Sap-C deficiency ................................................. 2068 3.12.5. Sap-D....................................................... 2068 4. Pathogenesis of spingolipidoses ................................................... 2069 5. Diagnosis .............................................................. 2070 6. Therapeutic approaches ....................................................... 2070 6.1. Enzyme replacement therapy (ERT) ............................................. 2070 6.2. Cell-mediated therapy (CMT) ................................................ 2070 6.3. Gene therapy ......................................................... 2070 6.4. Enzyme-enhancement therapy ................................................ 2071 6.5. Substrate reduction therapy (SRT) .............................................. 2071 Acknowledgements ............................................................ 2071 References ................................................................ 2071 1. Sphingolipid structure, function and biosynthesis [32]; for example, the highly immunogenic, non-human α- galactosylphytoceramide activates a subset of NKT cells. This Together with glycerophospholipids and cholesterol, sphin- glycosphingolipid from the marine sponge Agelas mauritianus golipids are building blocks of eukaryotic membranes. They are [21] has gained much interest as a potential drug in the treatment characterized by the presence of a sphingoid base within the of cancer and autoimmune diseases [22,23]. An endogenous hydrophobic part of the molecule. In sphingomyelin and the sphingolipid ligand for CD1d and important for the maturation glycosphingolipids, a phosphorylcholine or a carbohydrate of NKT-cells appears to be isoglobotriaosylceramide. This was moiety are bound to the terminal hydroxyl group of ceramide demonstrated by a deficiency of invariant NKT-cells in β- (N-acylsphingosine), respectively (Fig. 1) [1]. hexosaminidase B-deficient mice, the animal model of Sandhoff Glycosphingolipids display a high structural diversity and diseases, which cannot convert isoglobotetraosylceramide into can be classified into series, which are characteristic for a group isoglobotriaosylceramide [24]. of evolutionary related organisms [1]. On cellular surfaces, glycosphingolipids form characteristic patterns that are species- 1.1. Less precisely defined is the role of sphingolipids in cancer and cell-type specific and change with cell growth, differentia- [25] tion, viral transformation, ontogenesis, and oncogenesis [2].In the plasma membrane, they are believed to segregate into pre- Intermediates of sphingolipid metabolism appear to be existing microdomains [3,4], which are enriched in glycosyl- involved in the transduction of extracellular signals into the phosphatidylinositol-anchored proteins, sphingomyelin, and interior of cells. Ceramide can be released from sphingomyelin or cholesterol. These so-called lipid rafts [5,6] might constitute by de-novo synthesis in response to substances like vitamin D3, the physiological surroundings of many membrane proteins. tumor necrosis factor α, γ-interferon, or interleukin 1. In most cell Glycosphingolipids are essential for development and types, ceramide mediates antimitogenic responses such as cell survival of multicellular organisms [7]; they play a role in cell differentiation, cell cycle arrest, cell senescence or apoptosis [26]. adhesion phenomena [8,9] and in the regulation of membrane Also other intermediates of sphingolipid metabolism such as proteins. Thus, absence of ganglioside GM3 in vivo leads to sphingosine, sphingosylphosphorylcholine [27], sphingosine-1- enhanced insulin receptor phosphorylation and increased insulin phosphate and ceramide-1-phosphate [28,29], are regarded as sensitivity [10]. Correct sphingolipid processing is also vital for signalling substances. Accordingly, the benefit of pharmacologi- the barrier function of the human skin [11], where ceramides of cal interference with sphingolipid-mediated processes has been the stratum corneum contribute to the water permeability barrier. investigated for several diseases [30,31]. Skin ceramides occur in free form [12], or covalently linked to Not only sphingolipids–including the signalling substances proteins of the cornified envelope [13]. In addition to disorders sphingosine-1-phosphate and ceramide–contribute to many phy- caused by alterations of sphingolipid metabolism, sphingolipids siological and pathological processes, but also the proteins are involved in a variety of diseases [14]. In infectious diseases, operating in the sphingolipid pathway can serve different functions. sphingolipids serve, e.g., as pathogen receptors [15–17] and can For example, sphingolipid activator proteins are required for the control pathogen infection and host defense [18]. In the immune presentation of lipid antigens to CD1 molecules [32]. system, glycosphingolipids play a role as antigens (ABO- System, Forssman), but can also stimulate the generation of 1.2. Biosynthesis autoantibodies in postinfectious autoimmune diseases like Guillain–Barré or Miller–Fisher Syndromes [19,20]. They are The first steps of glycosphingolipid biosynthesis lead to the ligands for CD1d-restricted natural killer T-cells (NKT-cells) formation of ceramide at the cytoplasmic face of the ER T. Kolter, K. Sandhoff / Biochimica et Biophysica Acta 1758 (2006) 2057–2079 2059 Fig. 1. Structures of ganglioside GM2, bis(monoacylglycero)phosphate