title: The lysosomal degradation of neuromedin B is dependent on tripeptidyl peptidase-I: evidence for the impairment of neuropeptide degradation in late-infantile neuronal ceroid lipofuscinosis.
abstract: Late-infantile neuronal ceroid lipofuscinosis (CLN2), previously known as the late-infantile form of Batten disease, is a lysosomal storage disease which results from mutations in the gene that codes for tripeptidyl peptidase-I (TPP-I). This disease is characterised by progressive neurodegeneration in young children although the molecular mechanisms responsible for neuronal cell death are unclear. TPP-I is an exopeptidase which removes N-terminal tripeptides from small peptides, including several peptide hormones. We report that the degradation of the neuropeptide, neuromedin B, by mouse brain cells is restricted to lysosomes and that the pattern of degradation products is consistent with a predominant role for TPP-I. Neuromedin B is degraded by a similar pathway in a mouse neuronal cell line and also in cultured human fibroblasts. A specific inhibitor of TPP-I is able to abolish neuromedin B degradation in a variety of cell types. Fibroblasts from CLN2 patients, which are deficient in TPP-I activity, are unable to degrade neuromedin B. These observations suggest that TPP-I is the predominant proteolytic enzyme responsible for the intracellular degradation of neuromedin B. The inability of cells from CLN2 patients to degrade neuromedin B and other neuropeptides may contribute to the pathogenesis of the disease.
authors.affiliation: Department of Cellular Pathology, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Kopan
authors.forename: Uthayatharsini
authors.initials: U
authors.lastname: Sivasubramaniam
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Warburton
mesh_terms: D000626:Aminopeptidases; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015287:Neurokinin B / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D057057:Serine Proteases; D012867:Skin / Q000378:metabolism; D013997:Time Factors; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D010455:Peptides; C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; D015287:Neurokinin B; C038393:neuromedin B; D010450:Endopeptidases; D010447:Peptide Hydrolases; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human