title: Correction of peripheral lysosomal accumulation in mice with aspartylglucosaminuria by bone marrow transplantation.
abstract: OBJECTIVE
  Bone marrow transplantation has been shown to alleviate symptoms outside the CNS in many lysosomal storage diseases depending on the type and stage of the disease, but the effect on neurological symptoms is variable or still unclear. Aspartylglucosaminuria (AGU) is a lysosomal storage disease characterized by mental retardation, recurrent infections in childhood, hepatosplenomegaly and coarse facial features. Vacuolized storage lysosomes are found in all tissues of patients and uncleaved enzyme substrate is excreted in the urine. The recently generated AGU mouse model closely mimicks the human disease and serves as a good model to study the efficiency of bone marrow transplantation in this disease.
  
  
  METHODS
  Eight-week-old AGU mice were lethally irradiated and transplanted with bone marrow from normal donors. The AGA enzyme activity was measured in the liver and the brain and the degree of correction of tissue pathology was analyzed by light and electron microscopy. Reverse bone marrow transplantation (AGU bone marrow to wild-type mice) was also performed.
  
  
  RESULTS
  Six months after transplantation the AGA enzyme activity was 13% of normal in the liver, but only 3% in the brain. Tissue pathology was reversed in the liver and the spleen, but not in the brain and the kidney. The urinary excretion of enzyme substrate was diminished but still detectable. No storage vacuoles were found in the tissues after reverse transplantation, but subtle excretion of uncleaved substrate was detected in the urine.
  
  
  CONCLUSIONS
  Liver and spleen pathology of AGU was corrected by bone marrow transplantation, but there was no effect on lysosomal accumulation in the CNS and in the kidneys.
authors.affiliation: National Public Health Institute, Department of Human Molecular Genetics, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Laine
authors.forename: J
authors.initials: J
authors.lastname: Richter
authors.forename: C
authors.initials: C
authors.lastname: Fahlman
authors.forename: J
authors.initials: J
authors.lastname: Rapola
authors.forename: M
authors.initials: M
authors.lastname: Renlund
authors.forename: L
authors.initials: L
authors.lastname: Peltonen
authors.forename: S
authors.initials: S
authors.lastname: Karlsson
authors.forename: A
authors.initials: A
authors.lastname: Jalanko
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000652:urine; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D054880:Aspartylglucosaminuria; D001227:Aspartylglucosylaminase / Q000032:analysis / Q000235:genetics; D016026:Bone Marrow Transplantation; D001921:Brain / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology / Q000517:prevention & control; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D016464:Lysosomal Storage Diseases / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008247:Lysosomes / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000032:analysis; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D011828:Radiation Chimera; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000201:enzymology / Q000473:pathology; D014617:Vacuoles / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; C000009:N-acetylglucosaminylasparagine; D001227:Aspartylglucosylaminase; D000117:Acetylglucosamine