pepstatin and Leukodystrophy--Globoid-Cell

A recent study has shown mutations in CLN2 gene, that encodes a novel lysosomal pepstatin-insensitive proteinase (LPIP), in the pathophysiology of late-infantile neuronal ceroid lipofuscinosis (LINCL). We have measured the LPIP activities in brains from various forms of human neuronal ceroid lipofuscinoses (NCL), canine ceroid lipofuscinosis and other neurodegenerative disorders with a highly sensitive assay using a tetrapeptide Gly-Phe-Phe-Leu-amino-trifluoromethyl coumarin (AFC) as substrate. Brain LPIP has a pH optimum of 3.5 and an apparent km of 100 microM for the crude enzyme. The enzyme activity is totally absent in LINCL patients. Pronounced increase in the LPIP activity was seen in patients suffering from infantile (INCL), juvenile (JNCL) and adult (ANCL) forms of neuronal ceroid lipofuscinoses. LPIP activity was also found to be increased about two-fold in Alzheimer's disease when compared with normal or age-matched controls, while in globoidal-cell leukodystrophy (Krabbe's disease) it was similar to the normal controls. Although mannose-6-phosphorylated LPIP is increased 13-fold in brains of patients with JNCL, this form of LPIP did not have any enzyme activity. The mechanism by which LPIP activities are increased in a wide range of neurodegenerative diseases is unknown, although neuronal loss, followed by gliosis are common characteristics of these diseases.

Topics: Adult; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aminopeptidases; Animals; Brain; Child; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Dog Diseases; Dogs; Endopeptidases; Female; Humans; Leukodystrophy, Globoid Cell; Male; Mannose; Middle Aged; Neurodegenerative Diseases; Neuronal Ceroid-Lipofuscinoses; Pepstatins; Peptide Hydrolases; Reference Values; Serine Proteases; Tripeptidyl-Peptidase 1