title: Tripeptidyl-peptidase I in neuronal ceroid lipofuscinoses and other lysosomal storage disorders.
abstract: The classic late infantile form of neuronal ceroid lipofuscinosis (CLN2, cLINCL) is associated with mutations in the gene encoding tripeptidyl-peptidase I (TPP-I), a lysosomal aminopeptidase that cleaves off tripeptides from the free N-termini of oligopeptides. To date over 30 different mutations and 14 polymorphisms associated with CLN2 disease process have been identified. In the present study, we analysed the molecular basis of 15 different mutations of TPP-I by using immunocytochemistry, immunofluorescence, Western blotting, enzymatic assay and subcellular fractionation. In addition, we studied the expression of TPP-I in other lysosomal storage disorders such as CLN1, CLN3, muccopolysaccharidoses and GM1 and GM2 gangliosidoses. Our study shows that TPP-I is absent or appears in very small amounts not only in cLINCL subjects with mutations producing severely truncated protein, but also in individuals with missense point mutations, which correlates with loss of TPP-I activity. Of interest, small amounts of TPP-I were detected in lysosomal fraction from fibroblasts from cLINCL subject with protracted form. This observation suggests that the presence of small amounts of TPP-I in lysosomes is able to delay significantly CLN2 disease process. We also show that TPP-I immunoreactivity is increased in the brain tissue of CLN1 and CLN3 subjects, stronger in glial cells and macrophages than neurons. Less prominent increase of TPP-I staining was found in muccopolysaccharidoses and GM1 and GM2 gangliosidoses. These data suggest that TPP-I participates in lysosomal turnover of proteins in pathological conditions associated with cell/tissue injury.
authors.affiliation: Department of Pathological Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Wisniewski
authors.forename: E
authors.initials: E
authors.lastname: Kida
authors.forename: M
authors.initials: M
authors.lastname: Walus
authors.forename: P
authors.initials: P
authors.lastname: Wujek
authors.forename: W
authors.initials: W
authors.lastname: Kaczmarski
authors.forename: A A
authors.initials: AA
authors.lastname: Golabek
mesh_terms: D000626:Aminopeptidases; D000906:Antibodies; D001921:Brain / Q000201:enzymology; D002478:Cells, Cultured; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D010450:Endopeptidases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007223:Infant; D016464:Lysosomal Storage Diseases / Q000201:enzymology / Q000235:genetics; D008247:Lysosomes / Q000201:enzymology; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011110:Polymorphism, Genetic; D022821:RNA Splice Sites / Q000235:genetics; D057057:Serine Proteases; D012867:Skin / Q000166:cytology; D013347:Subcellular Fractions / Q000201:enzymology; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D000906:Antibodies; D022821:RNA Splice Sites; D000091346:Tripeptidyl-Peptidase 1; D010450:Endopeptidases; D010447:Peptide Hydrolases; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human