title: Juvenile and adult metachromatic leukodystrophy: partial restoration of arylsulfatase A (cerebroside sulfatase) activity by inhibitors of thiol proteinases.
abstract: Arylsulfatase A polypeptides were examined in cultured fibroblasts from a patient with juvenile metachromatic leukodystrophy and three patients with the adult form of the disease, with the aid of metabolic labeling and immunoprecipitation. The mutant cells were severely deficient in the arylsulfatase polypeptides. The apparent rate of synthesis, however, as estimated from the secretion of polypeptides or activity by cells incubated in the presence of 10 mM NH4Cl was 20-50% of control. In the absence of NH4Cl, the mutant enzyme was rapidly degraded upon transport into lysosomes. In the presence of inhibitors of thiol proteinases arylsulfatase A polypeptides were partially protected from degradation, and the catalytic activity of arylsulfatase A was increased. In addition, the treatment partially corrected the capacity of the cells to degrade cerebroside sulfates. Inhibitors of thiol proteinases may be of therapeutic value in variants of metachromatic leukodystrophy, in which an unstable arylsulfatase A is synthesized.
mesh_terms: D000328:Adult; D000367:Age Factors; D002402:Cathepsin D; D002403:Cathepsins / Q000235:genetics; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000235:genetics / Q000378:metabolism*; D002648:Child; D003546:Cysteine Endopeptidases; D004705:Endocytosis; D010450:Endopeptidases / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D007966:Leukodystrophy, Metachromatic / Q000201:enzymology* / Q000235:genetics; D008297:Male; D013429:Sulfatases / Q000378:metabolism*
chemical_list: D013429:Sulfatases; D002553:Cerebroside-Sulfatase; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002402:Cathepsin D