title: Mucolipidosis type IV: abnormal transport of lipids to lysosomes.
abstract: Mucolipidosis type IV (MLIV) is a lysosomal storage disorder in which various phospholipids and gangliosides accumulate. The cause of this storage has not yet been identified. Loading experiments in cultured fibroblasts with radioactive phosphatidylcholine ([14C]PC) labelled either in the acyl groups or in the choline residue, indicated increased retention of this lipid in the lysosomes of these patients. Chase experiments in intact fibroblasts, on the other hand, indicated normal degradation and discharge of the radioactive PC in MLIV lysosomes. This was further supported by measurements of the degradation of [14C]PC by isolated lysosomes which indicated normal breakdown of PC in MLIV. Cultured fibroblasts from Hunter (MPSII) patients, which contain enlarged and numerous lysosomes, did not store [14C]PC when compared to normal controls, indicating that the storage of this lipid in MLIV is not a secondary phenomenon caused by the presence of enlarged and numerous lysosomes in these cells. Incubation of [14C]PC at 18 degrees C limits the endocytosis process only up to early endosomes. This temperature did not yield increased retention of [14C]PC in MLIV, indicating that accumulation occurs only after the PC reached late endosomes or the lysosomes. The data indicate that PC as well as other phospholipids and gangliosides accumulate in MLIV apparently owing to a defect in the endocytosis process of membranous components. This defect apparently leads to excessive transportation of these macromolecules into lysosomes rather than their recycling to the plasma membrane. The endocytosis of membrane components is different from receptor-mediated endocytosis which is not affected in MLIV. Once the membrane macromolecules reach the lysosomes in MLIV they are normally catabolized and normally discharged. This may explain the heterogeneity of the stored materials in MLIV. The normal catabolism of macromolecules in the lysosomes is reflected in the minor deterioration in the clinical manifestations of these patients.
authors.affiliation: Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Bargal
authors.forename: G
authors.initials: G
authors.lastname: Bach
mesh_terms: D002478:Cells, Cultured; D004705:Endocytosis; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D009081:Mucolipidoses / Q000235:genetics*; D010713:Phosphatidylcholines / Q000378:metabolism*
chemical_list: D010713:Phosphatidylcholines