Friday 4 December 2009
New research sheds light on suitable animal models for Duchenne
New research results, from a project funded by the Muscular Dystrophy Campaign, will help scientists identify the most appropriate animal model for their research. The project studied the proteins associated with dystrophin - the protein missing in boys with Duchenne muscular dystrophy – and found that the mdx mouse model is not suitable when studying the effects of the missing dystrophin gene in the brain. Scientists found that there are big differences in the way mouse and human proteins work alongside dystrophin to make up the scaffold which is key for the structure of cells. This difference was particularly apparent in the brain. The researchers therefore suggested that the mouse is not a suitable model for studying the changes which happen in the brains of individuals with Duchenne muscular dystrophy, which can sometimes lead to learning difficulties. The differences between human and mouse muscle however were less striking, so it appears that the mdx mouse is still a useful model for studying and developing therapies for the muscle aspects of Duchenne muscular dystrophy.
Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. This gene contains the instructions for production of dystrophin protein which is an important structural component of cells throughout the body, especially muscle. However, dystrophin does not act alone- it forms a large scaffold with at least 10 other proteins. In the muscle this scaffold - called the 'dystrophin glycoprotein complex' - works as a shock absorber to prevent damage when the muscle contracts. Changes to any of the proteins in the scaffold can change its structure and stability. The function of the scaffold in other parts of the body such as the brain is less well understood.
In Duchenne muscular dystrophy no dystrophin protein is produced which causes the whole scaffold to fall apart. Mutations in other proteins of the scaffold cause other types of muscular dystrophy such as limb girdle muscular dystrophy. This new research investigated more subtle changes to the proteins in the scaffold which can change how it works.
Contents:
What does this new research show?
This research, led by Dr Roland Roberts at King's College London, looked at the main partner of dystrophin at the centre of the 'dystrophin glycoprotein complex' scaffold- a protein called alpha-dystrobrevin. The gene which contains the instructions for the alpha-dystrobrevin protein is very complex. It can instruct cells to make many slightly different types of alpha-dystrobrevin in different tissues of the body. This research examined the different types of alpha-dystrobrevin produced in different species of animal including humans and mice.
It was found that humans and other animals have evolved to be able to produce a wider range of alpha-dystrobrevins than mice or rats. These different alpha-dystrobrevins can change not only the structure or shape of the scaffold, but also recruit different proteins into the scaffold which can have an influence on its function.
In particular mice and rats are missing more than 50 percent of the alpha-dystrobrevin types present in human brains. Around a third of boys with Duchenne muscular dystrophy have learning difficulties. Scientists do not yet understand how the lack of dystrophin causes this problem, and this study has shown that mdx mice which are widely used as a model for Duchenne muscular dystrophy, may not be a suitable model for studying this aspect of the condition. However, other rodents such as the guinea pig appear to have more similar alpha-dystrobrevin types to humans so might be a more suitable model.
However, the differences between human and mouse skeletal and heart muscles were less striking, with only some differences in the amounts of the different types of alpha-dystrobrevin. So it appears that the mdx mouse is still a useful model for studying and developing therapies for the muscle aspects of Duchenne muscular dystrophy.
What does this mean for patients?
The use of animals in research has been crucial to understand what goes wrong in the body as a consequence of a genetic defect and most importantly to test the safety and efficiency of potential treatments. The differences between animals and humans however, can impact on the suitability of an animal model and it is important to understand the limitations.
Animal models are an important part of translational research ensuring a faster transfer of promising treatments into clinical trials. The mdx mouse has been extensively used to understand the function of the dystrophin protein in the muscle and to successfully test treatments that aim to improve muscle function. In the future, researchers might want to use animal models to address the function of the dystrophin gene in the brain and test treatments for the learning difficulties that affect some boys with Duchenne muscular dystrophy. The results of this study are giving researchers vital information that the mdx mouse is not the best model to study what happens in human brains.
Dr Roland Roberts, King's College London said:
The mouse has been a great model for many of the things that go wrong in Duchenne muscular dystrophy, but we've always known that it has certain limitations. What we show here, in our work funded by the Muscular Dystrophy Campaign, is that there are substantial reasons for doubting that the mouse is an adequate test-bed for the neurological aspects of Duchenne muscular dystrophy, such as learning difficulties. Mice and rats appear to have important bits missing from the gene that encodes alpha-dystrobrevin, a critical part of the dystrophin complex. Our findings suggest that a better "guinea pig" for investigating Duchenne muscular dystrophy-related learning difficulties might be... a guinea pig! This animal, although related to mice and rats, has an intact dystrobrevin gene like ours.
More information about Duchenne muscular dystrophy.
The original paper is freely available online but it is written in scientific language with no summary in layman's terms.
The reference for the paper is:
Boehm SV, Constantinou P, Tan S, Jin H and Roberts RG. Profound human/mouse differences in alpha-dystrobrevin isoforms: a novel syntrophin-binding site and promoter missing in mouse and rat. BMC Biology, 2009, 7:85.
