Amelioration of muscular dystrophy by transgenic expression of Niemann-Pick C1

Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystr...

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Bibliographic Details
Published in:Molecular biology of the cell 2009-01, Vol.20 (1), p.146-152
Main Authors: Steen, Michelle S, Adams, Marvin E, Tesch, Yan, Froehner, Stanley C
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
Dystrophin - genetics
Dystrophin - metabolism
Dystrophin-Associated Proteins - genetics
Dystrophin-Associated Proteins - metabolism
Gene Expression Profiling
Gene Expression Regulation
Humans
Lysosomes - metabolism
Male
Mice
Mice, Inbred mdx
Mice, Transgenic
Muscle, Skeletal - cytology
Muscle, Skeletal - pathology
Muscle, Skeletal - physiology
Muscular Dystrophy, Duchenne - genetics
Muscular Dystrophy, Duchenne - metabolism
Oligonucleotide Array Sequence Analysis
Phenotype
Proteins - genetics
Proteins - metabolism
Transgenes
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Summary:Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking alpha-dystrobrevin (Dtna(-/-)), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna(-/-) mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E08-08-0811