Sphingolipid metabolism diseases

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.

Phosphoregulation of the Ceramide Transport Protein CERT at Serine 315 in the Interaction with VAMP-associated Protein (VAP) for Inter-organelle Trafficking of Ceramide in Mammalian Cells

“…Lactosylceramide was from Nagara Science (Gifu, Japan). Ricinus communis lectin (RCA 120) was from Vector Laboratories Inc. N-[palmitoyl- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]Palmitoyl-Derythro-sphingosine ([ 14 C]ceramide) (55 mCi/mmol) was from American Radiolabeled Chemicals. ISP-1/myriocin (16) was a gift from Dr. Tetsuro Fujita (Research Institute for Production Development, Japan).…”

“…Ceramide is also converted to glucosylceramide at the cis-Golgi region and/or a subregion of the ER (6). Glucosylceramide is converted to more complex glycosphingolipids in the medial/ trans-Golgi regions (7,8). The transport of ceramide from the ER to the Golgi site for the synthesis of SM is mediated by the ceramide transport protein CERT, a cytosolic 70-kDa protein (3,9).…”

The sphingolipid salvage pathway in ceramide metabolism and signaling

“…Genetic defects in several of these hydrolytic enzymes cause various disorders with lysosomal accumulation of the substrate lipids, a group of disorders termed the sphingolipidoses [41,[90][91][92][93]. Particularly, some of the known sphingolipidoses might closely associate with aberrant metabolisms of ceramide because of defective activities of ceramide generating/degrading enzymes: Farber's disease, Gaucher disease, and Niemann-Pick type A and B diseases are caused by a deficiency of acid ceramidase [94,95], glucocerebrosidase (acid-β-glucosidase) [96][97][98], acid SMase [99,100], respectively.…”

Sphingolipids and membrane biology as determined from genetic models

“…Krabbe disease is caused by the absence of galactocerebrosidase in humans and results in central and peripheral neurodegeneration [131,132]. The mouse model for Krabbe disease, caused by a defect in the homologous gene, die before the age of mating.…”