Lysosomal enzymes are synthesized as soluble or membrane-integrated glycoproteins in the rough endoplasmic reticulum (ER). In mammalian cells mannose 6-phosphate receptors (MPRs) mediate the transport of the majority of lysosomal enzymes to lysosomes. Mannose 6-phosphate (Man-6-P) terminal residues are recognized in the trans-Golgi network (TGN) by two MPRs which mediate the sorting of lysosomal enzymes from the secretory pathway and deliver them to a prelysosomal compartment from where the receptors return to the TGN and the ligands are forwarded to dense lysosomes (reviewed in (Kornfeld, 1992; Kornfeld and Mellman, 1989; Ludwig et al., 1995)). The physiological importance of the MPR-dependent transport of lysosomal enzymes is illustrated by I-cell disease (ICD). In this disorder, the deficiency of the phosphotransferase responsible for catalyzing the addition of Man-6-P results in the synthesis of lysosomal enzymes that lack Man-6-P residues leading to a failure to bind to MPRs and a strongly increased secretion of most of the lysosomal enzymes (Neufeld, 1991). Although fibroblasts of these patients have a marked deficiency of lysosomal enzymes, liver, spleen, kidney and brain tissues have nearly normal levels of lysosomal hydrolases (Kornfeld, 1986; Kornfeld and Sly, 1985). It was therefore proposed that in addition to MPR-dependent mechanisms, MPR-independent mechanisms are likely to exist for the transport of newly synthesized lysosomal enzymes to lysosomes (Ahn et al., 2002; Ginsel and Fransen, 1991; Glickman and Kornfeld, 1993; Rijnboutt et al., 1991; Tanaka et al., 2000). Also in MPR-deficient mice an ICD-like phenotype with increase of lysosomal enzymes in serum and normal activities in some tissues has been described (Dittmer et al., 1999).
In fibroblasts of ICD patients the lysosomal hydrolase β-glucocerebrosidase (βGC) has been shown to be intracellularly retained suggesting that signals other than Man-6-P are responsible for targeting this enzyme (Aerts et al., 1988; van Dongen et al., 1985). Mutations within the gene coding for human βGC are the cause of the most common lysosomal storage disorder, Gaucher Disease, in which the defective enzyme leads to an accumulation of glucosylceramide (GlcCer) (Beutler, 1991, 2006). Although the clinical course of this disease has been well described and an efficient treatment option, enzyme replacement therapy, is available little is known about how GlcCer accumulation in lysosomes leads to cellular pathology. Also the mechanism by which βGC is targeted from its site of synthesis in the ER to lysosomes is not well understood.
Thus, a greater understanding of the mechanism by which β-GC is targeted from its site of synthesis in the endoplasmic reticulum to lysosomes could lead to improved methods of treating lysosomal storage disorders such as Gaucher Disease.