A novel mouse model of a patient mucolipidosis II mutation recapitulates disease pathology.

Abstract

Mucolipidosis II (MLII) is a lysosomal storage disorder caused by loss of N-acetylglucosamine-1-phosphotransferase, which tags lysosomal enzymes with a mannose 6-phosphate marker for transport to the lysosome. In MLII, the loss of this marker leads to deficiency of multiple enzymes and non-enzymatic proteins in the lysosome, leading to the storage of multiple substrates. Here we present a novel mouse model of MLII homozygous for a patient mutation in the GNPTAB gene. Whereas the current gene knock-out mouse model of MLII lacks some of the characteristic features of the human disease, our novel mouse model more fully recapitulates the human pathology, showing growth retardation, skeletal and facial abnormalities, increased circulating lysosomal enzymatic activities, intracellular lysosomal storage, and reduced life span. Importantly, MLII behavioral deficits are characterized for the first time, including impaired motor function and psychomotor retardation. Histological analysis of the brain revealed progressive neurodegeneration in the cerebellum with severe Purkinje cell loss as the underlying cause of the ataxic gait. In addition, based on the loss of Npc2 (Niemann-Pick type C 2) protein expression in the brain, the mice were treated with 2-hydroxypropyl-β-cyclodextrin, a drug previously reported to rescue Purkinje cell death in a mouse model of Niemann-Pick type C disease. No improvement in brain pathology was observed. This indicates that cerebellar degeneration is not primarily triggered by loss of Npc2 function. This study emphasizes the value of modeling MLII patient mutations to generate clinically relevant mouse mutants to elucidate the pathogenic molecular pathways of MLII and address their amenability to therapy.

• Authors: Leigh Paton, Emmanuelle Bitoun, Janet Kenyon, David A Priestman, Peter L Oliver, Benjamin Edwards, Frances M Platt, Kay E Davies
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 39 Pg. 26709-26721 (Sep 26 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25107912 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Carrier Proteins
• Excipients
• Glycoproteins
• NPC2 protein, human
• Npc2 protein, mouse
• Vesicular Transport Proteins
• beta-Cyclodextrins
• 2-Hydroxypropyl-beta-cyclodextrin
• Transferases (Other Substituted Phosphate Groups)
• GNPTAB protein, human
• GNPTAB protein, mouse

Topics

• 2-Hydroxypropyl-beta-cyclodextrin
• Animals
• Behavior, Animal
• Carrier Proteins (genetics, metabolism)
• Disease Models, Animal
• Excipients (pharmacology)
• Glycoproteins (genetics, metabolism)
• HEK293 Cells
• Homozygote
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Mutant Strains
• Mucolipidoses (enzymology, genetics, pathology)
• Mutation
• Niemann-Pick Disease, Type C (enzymology, genetics, pathology)
• Purkinje Cells (enzymology, pathology)
• Transferases (Other Substituted Phosphate Groups) (genetics, metabolism)
• Vesicular Transport Proteins (genetics, metabolism)
• beta-Cyclodextrins (pharmacology)