Analyses of alpha-dystrobrevin-null mice implicate Niemann-Pick C1 in muscular dystrophy

Thesis (Ph. D.)--University of Washington, 2008.In skeletal muscle, the dystrophin-associated protein complex (DPC) links the intracellular actin cytoskeleton to the extracellular matrix. Duchenne muscular dystrophy (DMD) and various other muscular dystrophies are caused by the loss or alteration of certain proteins of the DPC. Abnormalities of the neuromuscular junction (NMJ) are also caused by the loss of various DPC proteins. We performed gene expression analyses on skeletal muscles from mice lacking the DPC members alpha-dystrobrevin (Dtna) or alpha-syntrophin (Snta) in order to identify molecular alterations that result in muscular dystrophy and/or NMJ abnormalities. We identified a highly significant reduction in Niemann-Pick C1 (Npc1) transcript levels in Dtna-/- compared to wild-type mice. Mutations in Npc1, a cholesterol- and sphingolipid-trafficking protein, cause a progressive, neurodegenerative lysosomal storage disorder (NPC disease). We generated transgenic mice expressing NPC1 exclusively in skeletal muscles of Dtna-/- and mdx (dystrophin-null) mice and found a significant attenuation of the dystrophic phenotype in both the Dtna-/- and mdx mice. We also observed a significant improvement of the NPC phenotype in a line of NPC1-null mice possessing the Npc1 transgene. The expression of transgenic NPC1 in skeletal muscle does not appear to explain the phenotypic improvement of the NPC1-null mice, but the insertion of the transgene into the chromosome may have physically affected a gene encoding a protein capable of modulating the phenotype of the disease. In conclusion, this research suggests a connection between altered NPC1 levels and muscular dystrophy, a connection that could lead to novel therapies for this grievous illness with few treatment options