Abstract

Muscular dystrophies are among the most common human genetic diseases and are characterized by progressive muscle degeneration. Muscular dystrophies result from genetic defects in components of the dystrophin-glycoprotein complex (DGC), a multimeric complex found in the muscle cell plasma membrane. The DGC links the intracellular cytoskeleton to the extracellular matrix and is thought to be important for maintaining the mechanical integrity of muscles and organizing signalling molecules. The exact role of the DGC in the pathogenesis of disease has, however, remained uncertain. Mutations in Caenorhabditis elegans DGC genes lead to specific defects in coordinated movement and can also cause muscle degeneration. Here we show that mutations in the gene snf-6 result in phenotypes indistinguishable from those of the DGC mutants, and that snf-6 encodes a novel acetylcholine/choline transporter. SNF-6 mediates the uptake of acetylcholine at neuromuscular junctions during periods of increased synaptic activity. SNF-6 also interacts with the DGC, and mutations in DGC genes cause a loss of SNF-6 at neuromuscular junctions. Improper clearing of acetylcholine and prolonged excitation of muscles might contribute to the pathogenesis of muscular dystrophies.

View details for DOI 10.1038/nature02798

View details for Web of Science ID 000223369800042

View details for PubMedID 15318222