Investigating the role of the dystroglycan protein
Project leader: Prof. Steve Winder
Location: University of Sheffield
Condition: Duchenne muscular dystrophy and the dystroglycanopathies
Start date: October 2009
End date: September 2013
Total project cost: £100,772
Official title: Regulation of dystroglycan function
Prof. Steve Winder at the University of Sheffield will supervise this studentship aimed at investigating the function of a protein called dystroglycan in healthy muscle and in Duchenne muscular dystrophy. Dystroglycan normally works together with dystrophin and other proteins to act as a scaffold to stabilize the structure of muscle cells. Without dystrophin- as is the case in Duchenne muscular dystrophy- the stabilizing scaffold, including dystroglycan is lost from the cells. Prof Winder will investigate whether making small changes to the dystroglycan molecule can help it to be retained in the muscle cells and consequently restore some stability to the muscle fibres. This approach will be used to investigate if there is potential as a future therapy for Duchenne muscular dystrophy
- What are the researchers aiming to do?
- How will the outcomes of the research benefit patients?
- Further information and links
Duchenne muscular dystrophy is caused by a mutation in the gene that carries the instructions for a protein called dystrophin. Dystrophin is an important structural protein in muscle and forms part of a larger network of proteins called the dystrophin-associated glycoprotein complex (DGC). Dystroglycan is also part of the DGC and together they act to give the muscle structural stability when it contracts. The loss of dystrophin in Duchenne muscular dystrophy can also lead to a loss of dystroglycan in the DGC. The loss of these proteins means that the structural scaffolding inside the muscle cell is not as strong as normal and so the muscle becomes damaged when it is contracting leading eventually to the muscle weakness and wasting seen in Duchenne muscular dystrophy.
Work carried out by a number of different scientists has suggested that if dystroglycan function can be restored in Duchenne muscular dystrophy, it might be possible to slow the progression of the disease. By restoring dystroglycan to the DGC, some of the muscle stability would be regained. Prof Winder and his student aim to investigate this theory.
The researchers will use genetic models and cultured muscle cells in order to determine how healthy cells control the function of the dystroglycan protein. This will give them information that could help them to manipulate dystroglycan in established models of muscular dystrophy. Prof Winder will investigate whether increasing the amount of functioning dystroglycan in the muscle can help prevent or slow down the progression of some of the symptoms of Duchenne muscular dystrophy or other muscular dystrophies where the dystroglycan protein is affected.
This particular piece of work is focusing on the role of dystroglycan in normal muscle and Duchenne muscular dystrophy. It may provide proof of principle that by increasing the amount of functional dystroglycan protein in Duchenne muscular dystrophy, muscle damage can be prevented or slowed. Providing proof of principle is an important step in the development of possible treatments. Although a number of potential therapies for Duchenne muscular dystrophy are in development, it is important to explore other avenues since it may be more beneficial for patients to receive combinations of therapies rather than a single drug.
Dystroglycan is an important protein found in muscle as well as other cell types. It is located in the outside layer of the cell known as the membrane, which separates the inside of the cell from the outside environment and controls what enters and exits the cell. Together with a number of other proteins in the muscle dystroglycan forms part of the dystrophin-associated glycoprotein complex (DGC). The role of the DGC in muscle is to provide a link between the structural elements inside the cell - the cytoskeleton - and the outside environment - the extracellular matrix. This has two functions. The first is to provide the muscle cell with structural stability when it contracts and the second is to provide the cell with information, via signals from the extracellular matrix, about its shape and polarity - ie. which way up it is. Mutations in several of the genes that carry the instructions for the proteins in the DGC have been associated with different types of muscle disease.
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