title: Neuronal sphingolipidoses: Membrane lipids and sphingolipid activator proteins regulate lysosomal sphingolipid catabolism.
abstract: Glycosphingolipids and sphingolipids of cellular plasma membranes (PMs) reach luminal intra-lysosomal vesicles (LVs) for degradation mainly by pathways of endocytosis. After a sorting and maturation process (e.g. degradation of sphingomyelin (SM) and secretion of cholesterol), sphingolipids of the LVs are digested by soluble enzymes with the help of activator (lipid binding and transfer) proteins. Inherited defects of lipid-cleaving enzymes and lipid binding and transfer proteins cause manifold and fatal, often neurodegenerative diseases. The review summarizes recent findings on the regulation of sphingolipid catabolism and cholesterol secretion from the endosomal compartment by lipid modifiers, an essential stimulation by anionic membrane lipids and an inhibition of crucial steps by cholesterol and SM. Reconstitution experiments in the presence of all proteins needed, hydrolase and activator proteins, reveal an up to 10-fold increase of ganglioside catabolism just by the incorporation of anionic lipids into the ganglioside carrying membranes, whereas an additional incorporation of cholesterol inhibits GM2 catabolism substantially. It is suggested that lipid and other low molecular modifiers affect the genotype-phenotype relationship observed in patients with lysosomal diseases.
authors.affiliation: University of Bonn, LIMES Institute, c/o Kekulé-Institute, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany. Electronic address: sandhoff@uni-bonn.de.
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
mesh_terms: D002784:Cholesterol / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism*; D008954:Models, Biological; D049128:Sphingolipid Activator Proteins / Q000378:metabolism*; D013106:Sphingolipidoses / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: D008563:Membrane Lipids; D049128:Sphingolipid Activator Proteins; D013107:Sphingolipids; D002784:Cholesterol
keywords: Cholesterol transfer of NPC2; Lipid modifiers; Regulation of acid sphingomyelinase; Regulation of ganglioside catabolism; Tay Sachs disease