Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in lysosomal tripeptidyl peptidase I

Tripeptidyl peptidase I (TPP-I) is a lysosomal enzyme that cleaves tripepti des from the N-terminus of polypeptides. A comparison of TPP-I amino acid s equences with sequences derived from an EST database suggested that TPP-I i s identical to a pepstatin-insensitive carboxyl proteinase of unknown speci ficity which is mutated in classical late infantile neuronal ceroid lipofus cinosis (LINCL), a lysosomal storage disease, Both TPP-I and the carboxyl p roteinase have an M-r of about 46 kDa and are, or are predicted to be, resi stant to inhibitors of the four major classes of proteinases. Fibroblasts f rom LINCL patients have less than 5% of the normal TPP-I activity. The acti vities of other lysosomal enzymes, including proteinases, are in the normal range, LINCL fibroblasts are also defective at degrading short polypeptide s and this defect can be induced in normal fibroblasts by treatment with a specific inhibitor or TPP-I. These results suggest that the cell damage, es pecially neuronal, observed in LINCL results from the defective degradation and consequent lysosomal storage of small peptides. (C) 1999 Federation of European Biochemical Societies.