MUCOLIPIDOSIS TYPE-IV - ABNORMAL TRANSPORT OF LIPIDS TO LYSOSOMES

Mucolipidosis type IV (MLIV) is a lysosomal storage disorder in which various phospholipids and gangliosides accumulate. The cause of this s torage has not yet been identified. Loading experiments in cultured fi broblasts with radioactive phosphatidylcholine ([C-14]PC) labelled eit her in the acyl groups or-in the choline residue, indicated increased retention of this lipid in the lysosomes of these patients. Chase expe riments in intact fibroblasts; on the other hand; indicated,normal deg radation and discharge of the radioactive PC in MLIV lysosomes. This w as further supported by measurements of the;degradation of [C-14]PC by isolated lysosomes which indicated normal breakdown of PC in MLIV. Cu ltured fibroblasts from Hunter (MPSII) patients, which contain enlarge d and numerous lysosomes, did not store [C-14]PC when compared to norm al 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 [C-14]PC at 18 degrees C limi ts the endocytosis process only up to early endosomes. This temperatur e did not yield increased retention of [C-14]PC in MLIV, indicating th at accumulation occurs only after the PC reached late endosomes or the lysosomes. The data indicate that PC as well as other phospholipids a nd:gangliosides accumulate in MLIV apparently owing to a defect in the endocytosis process of membranous components. This defect apparently leads tb excessive transportation of these macromolecules into lysosom es rather than their recycling to the plasma membrane. The endocytosis of membrane components is different from receptor mediated endocytosi s which is not affected in MLIV. Once the membrane macromolecules reac h the lysosomes in MLIV they are, normally catabolized and normally di scharged. This may explain the heterogeneity of the stored materials i n MLIV. The normal catabolism of macromolecules in the lysosomes is re flected in the minor deterioration in the clinical manifestations of t hese patients.