LYSOSOMAL BIOGENESIS IN LYSOSOMAL STORAGE DISORDERS

Lysosomal biogenesis is an orchestration of the structural and functio nal elements of the lysosome to form an integrated organelle and invol ves the synthesis, targeting, functional residence, and turnover of th e proteins that comprise the lysosome. We have investigated lysosomal biogenesis during the formation and dissipation of storage vacuoles in two model systems. One involves the formation of sucrosomes in normal skin fibroblasts and the other utilizes storage disorder-affected ski n fibroblasts; both of these systems result in an increase in the size and the number of lysosomal vacuoles. Lysosomal proteins, beta-hexosa minidase, alpha-mannosidase, N-acetylgalactosamine-4-sulfatase, acid p hosphatase, and the lysosome-associated membrane protein, LAMP-1, were shown to be elevated between 2- and 28-fold above normal during lysos omal storage. Levels of mRNA for the lysosome-associated membrane prot eins LAMP-1 and LAMP-P, N-acetylgalactosamine-4-sulfatase, and the 46- and 300-kDa mannose-6-phosphate receptors were also elevated 2- to 8- fold. The up-regulation of protein and mRNA lagged 2-4 days behind the formation of lysosomal storage vacuoles. Correction of storage, in bo th systems, resulted in the rapid decline of the mRNA to basal levels, with a slower decrease in the levels of lysosomal proteins. Lysosomal biogenesis in storage disorders is shown to be a regulated process wh ich is partially controlled at, or prior to, the level of mRNA. Althou gh lysosomal proteins were differentially regulated, the coordination of these events in lysosomal biogenesis would suggest that a common me chanism(s) may be in operation. (C) 1997 Academic Press.