title: Protein catabolism in fibroblasts cultured from patients with mucolipidosis II and other lysosomal disorders.
abstract: Protein catabolism in fibroblasts cultured from the skin of normal individuals and of patients with mucolipidosis II (I-cell disease) and several other lysosomal storage diseases was examined by metabolic labelling with [3H]leucine and following the fate of radioactive proteins in pulse-chase experiments. In mucolipidosis II cells, overall protein degradative rates were found to be distinctly lower than in normal control cells. To distinguish lysosomal from non-lysosomal degradation, labelling experiments were carried out in the presence and absence of 10 mM NH4Cl, an inhibitor of lysosomal function. It was found that mucolipidosis II fibroblasts exhibited a markedly reduced rate of lysosomal protein degradation, whereas the rate of nonlysosomal degradation appeared normal. Serum and amino acid starvation led to a marked increase in lysosomal protein degradation in normal cells, but had only a minimal effect on that in mucolipidosis II fibroblasts. The specific activities of cathepsins B, H and L were profoundly diminished in all mucolipidosis II cell lines tested. Lysosomal protein degradation in a mucolipidosis III cell line was impaired to a similar degree as in mucolipidosis II cells, whereas it was decreased to a lesser extent in fibroblasts from patients with mucopolysaccharidoses I and VI, galactosialidosis and GM1-gangliosidosis. We conclude that fibroblasts from patients with mucolipidosis II and III have a severely compromised capacity for endogenous lysosomal protein degradation that appears to result from multiple cathepsin deficiency. This lysosomal defect is likely to have pathophysiological consequences.
authors.affiliation: Institute of Pathochemistry and General Neurochemistry, University of Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kopitz
authors.forename: A
authors.initials: A
authors.lastname: Arnold
authors.forename: T
authors.initials: T
authors.lastname: Meissner
authors.forename: M
authors.initials: M
authors.lastname: Cantz
mesh_terms: D002401:Cathepsin B / Q000378:metabolism; D056655:Cathepsin H; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000201:enzymology / Q000378:metabolism*; D009081:Mucolipidoses / Q000201:enzymology / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*
chemical_list: D011506:Proteins; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534126:CTSH protein, human; D056655:Cathepsin H