ABSTRACT
The mannose-6-phosphate receptors (MPRs) play an essential role in the formation of functional lysosomes by directing newly synthesized soluble acid hydrolases containing a mannose 6-phosphate (Man-6-P) tag to lysosomes. The importance of this targeting process in the generation of lysosomes containing a full-complement of hydrolytic enzymes is evidenced by the existence of over 40 different lysosomal storage diseases (LSDs) [1-3]. LSDs constitute a signi cant portion of inborn metabolic disorders: Although individually rare, the collective frequency of LSDs is estimated to be approximately 1 in 8000 live births [4]. The majority of LSDs are caused by a de ciency of a single lysosomal enzyme that results in the accumulation or storage of undigested endogenous macromolecules within lysosomes, with the defective lysosomes appearing as phase-dense inclusions in the cytoplasm. How the accumulation of macromolecules in lysosomes leads to progressive cellular and organ dysfunction and to the enormous heterogeneity of clinical phenotypes observed in LSD patients remains an unanswered question [3]. In vitro cell culture studies demonstrating that the addition of exogenous enzyme to broblasts from LSD patients could decrease the intracellular accumulation of stored products in lysosomes [5-7] paved the way for the treatment of patients by enzyme replacement therapy. In these patients, lysosomal storage can be partially or completely reversed in many target tissues by intravenous injection, typically on a weekly basis, of the missing lysosomal enzyme, and the injected enzyme is internalized by receptor-mediated endocytosis via endogenous receptors. To date, three (Fabry disease, Mucopolysaccharidosis I, and Pompe disease) out of the four Food and Drug Administration
(FDA)-approved enzyme replacement therapies target the MPRs for uptake of the infused Man-6-Pcontaining enzyme [8]. Understanding the molecular basis of how MPRs function in the biogenesis of lysosomes is of fundamental importance in the development of new and improved therapies for the treatment of LSDs.
