期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 101, 期 34, 页码 12658-12663出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0405042101
关键词
beta-glucuronidase; mannose 6-phosphate/insulin-like growth factor II; receptor; central nervous system; lysosomal storage disease; phosphorylated beta-glucuronidase
资金
- NIAAA NIH HHS [R01 AA 12743, R01 AA012743] Funding Source: Medline
- NIGMS NIH HHS [R01 GM 34182, R01 GM034182] Funding Source: Medline
- NINDS NIH HHS [R01 NS041863, R01 NS 41863] Funding Source: Medline
Mucopolysaccharidosis type VII is a lysosomal storage disorder resulting from inherited deficiency of beta-glucuronidase (GUS). Mucopolysacchariclosis 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. I-131-P-GUS was transported across the BBB after i.v. injection in 2-day-old mice. The brain influx rate (K-in) of I-131-P-GUS in 2-day-old mice was 0.21 mul/g(.)min and decreased with age. By 7 weeks of age, transport of I-131-P-GUS was not significant. Capillary depletion revealed that 62% of the I-113-P-GUS in brain was in brain parenchyma in 2-day-old mice. In addition, uptake of I-131-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 I-131-NP-GUS (0.04 mul/g(.)min) was significantly lower than I-131-P-GUS in 2-day-old mice. Transcardiac brain perfusion confirmed that neither I-131-P-GUS nor I-131-NP-GUS crossed the BBB in adult mice. These results indicate that I-131-p-GUS transport into brain parenchyma in early postnatal life is mediated by the mannose 6-phosphate/insulin-like growth factor 11 receptor. This receptor-mediated transport is not observed in adult mice.
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