Dystrophin Associated Proteins in Synapse Formation and Muscular Dystrophy
Dystrophin is a cytoskeletal protein that is linked to dystroglycan in the plasma membrane to form the functional core of a larger, supramolecular complex that is expressed in muscle, brain and other tissues. Mutations in dystrophin and dystroglycan result in muscular dystrophies as well as in defects in neuromuscular synapses. Duchenne Muscular Dystrophy, which results from mutations in the dystrophin gene, often is accompanied by some mental retardation. Work from the Carbonetto lab is aimed at understanding the role of dystroglycan, dystrophin and associated proteins in muscle function/dysfunction, and in synaptic transmission. These studies require a range of techniques from protein biochemistry, to immunohistochemistry, recombinant DNA approaches and targeted mutations in mice. Research on muscle function focus on how dystroglycan maintains muscle integrity. Mutational analysis of the dystroglycan gene in a transgenic mouse model will identify regions of the protein which are implicated in muscular dystrophy. Other work is aimed at the pathways of cell death regulated by dystroglycan in muscle cells in culture. Studies on synapses utilize the neuromuscular junction as a model to explore how dystroglycan stabilizes acetylcholine receptors and acetylcholinesterase in the postsynaptic membrane. In addition dystroglycan levels regulate nerve terminal size. Thus changes in this complex may well be important in changes responsible for synaptic plasticity. Finally, we have identified a novel complex of dystrophin associated proteins in the brain which functions synaptically in vesicle recycling and may be relevant to the mental retardation associated with some muscular dystrophies.