Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier.

Abstract

Mucopolysaccharidosis type VII is a lysosomal storage disorder resulting from inherited deficiency of beta-glucuronidase (GUS). Mucopolysaccharidosis type VII is characterized by glycosaminoglycan storage in most tissues, including brain. In these disorders, enzyme delivery across the blood-brain barrier (BBB) is the main obstacle to correction of lysosomal storage in the CNS. Prior studies suggested mouse brain is accessible to GUS in the first 2 weeks of life but not later. To explore a possible role for the mannose 6-phosphate/insulin-like growth factor II receptor in GUS transport across the BBB in neonatal mice, we compared brain uptake of phosphorylated GUS (P-GUS) and nonphosphorylated GUS (NP-GUS) in newborn and adult mice. (131)I-P-GUS was transported across the BBB after i.v. injection in 2-day-old mice. The brain influx rate (K(in)) of (131)I-P-GUS in 2-day-old mice was 0.21 microl/g.min and decreased with age. By 7 weeks of age, transport of (131)I-P-GUS was not significant. Capillary depletion revealed that 62% of the (131)I-P-GUS in brain was in brain parenchyma in 2-day-old mice. In addition, uptake of (131)I-P-GUS into brain was significantly reduced by coinjection of unlabeled P-GUS or M6P in a dose-dependent manner. In contrast, the K(in) of (131)I-NP-GUS (0.04 microl/g.min) was significantly lower than (131)I-P-GUS in 2-day-old mice. Transcardiac brain perfusion confirmed that neither (131)I-P-GUS nor (131)I-NP-GUS crossed the BBB in adult mice. These results indicate that (131)I-P-GUS transport into brain parenchyma in early postnatal life is mediated by the mannose 6-phosphate/insulin-like growth factor II receptor. This receptor-mediated transport is not observed in adult mice.

• Authors: Akihiko Urayama, Jeffrey H Grubb, William S Sly, William A Banks
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 34 Pg. 12658-63 (Aug 24 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15314220 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Iodine Radioisotopes
• Receptor, IGF Type 2
• Recombinant Proteins
• Serum Albumin
• Glucuronidase

Topics

• Animals
• Animals, Newborn
• Blood-Brain Barrier (physiology)
• Brain (metabolism)
• Glucuronidase (genetics, metabolism)
• Humans
• Iodine Radioisotopes (metabolism)
• Lysosomes (enzymology)
• Male
• Mice
• Mice, Inbred Strains
• Protein Transport (physiology)
• Receptor, IGF Type 2 (metabolism)
• Recombinant Proteins (genetics, metabolism)
• Serum Albumin (metabolism)
• Time Factors