期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：34
页码：12658-12663
DOI：10.1073/pnas.0405042101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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. 131I-P-GUS was transported across the BBB after i.v. injection in 2-day-old mice. The brain influx rate (Kin) of 131I-P-GUS in 2-day-old mice was 0.21 {micro}l/g{middle dot}min and decreased with age. By 7 weeks of age, transport of 131I-P-GUS was not significant. Capillary depletion revealed that 62% of the 131I-P-GUS in brain was in brain parenchyma in 2-day-old mice. In addition, uptake of 131I-P-GUS into brain was significantly reduced by coinjection of unlabeled P-GUS or M6P in a dose-dependent manner. In contrast, the Kin of 131I-NP-GUS (0.04 {micro}l/g{middle dot}min) was significantly lower than 131I-P-GUS in 2-day-old mice. Transcardiac brain perfusion confirmed that neither 131I-P-GUS nor 131I-NP-GUS crossed the BBB in adult mice. These results indicate that 131I-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.
关键词：β-glucuronidase ; mannose 6-phosphate/insulin-like growth factor II receptor ; central nervous system ; lysosomal storage disease ; phosphorylated β-glucuronidase
