While mice are invaluable tools to study a range of human diseases, their small size can sometimes belie the huge difficulty researchers face when attempting to model complex human neurological disorders. Aside from the challenges relating to the sheer difference in the size of the nerves, the molecular changes that cause disease in humans are often very hard to mimic. "The strategy that people are generally using is to generate targeted mutants with a knockout gene and then just study the effects," says Martin Koltzenberg, a professor of clinical neurophysiology at the University College London's Institute of Neurology. "And while that is often conceptually clearer, it actually doesn't simulate the situation in humans where you have single amino acid changes often that then causes a phenotype."
But a large-scale collaboration between the University College London, the Medical Research Centre Harwell, the University of Oxford, the University of London in England, Vrije University in the Netherlands, and The Jackson Laboratory in Maine has made a dent in this problem. Recently, Koltzenberg and his collaborators unveiled an effective mouse model for the study of nervous system diseases Charcot-Marie-Tooth and hereditary motor neuropathy. By making a mutation in a protein called glycyl-tRNA synthetase (GARS), the group created mice with many of the same symptoms caused by Charcot-Marie-Tooth and hereditary motor neuropathy. According to the group, this is the first example of successful breeding of an animal with the GARS mutation.
One of the biggest hurdles they faced during the project was the lack of an effective means to help analyze how the animal is affected. "If I had a patient who presents some neurological abnormalities here at my hospital I would be able to send them to lots of different consultants with different subspecialties in neurology, but that is something we really don't have for mouse," Koltzenberg says. "So what we really need to develop is something like a mouse hospital where if you have mutant animals you can easily have them analyzed."
The required breadth of testing is why the collaboration included so many institutions. "What we face at the moment, both in America and Europe, is that a lot of funding is going into knocking out every single gene in the mouse so people can generate mutant mice, but the big problem is that there are relatively few people around who can analyze these animals," Koltzenberg says. "Some of these techniques are very sophisticated and there are very few places that can do that kind of analysis. And that is a big problem right now, so getting all the tests lined up so that they can be done efficiently and you can look at places where you may not see any pathology is a nontrivial challenge."