Scientists develop mutant zebrafish to study Maple Syrup Urine Disease

Published on February 14, 2012 at 1:39 AM · 1 Comment

In medical research, finding a reliable and cost-effective animal model can greatly enhance success in identifying disease mechanisms and genetic pathways, potentially cutting years off drug testing regimes and development of new treatment strategies.

Now, University of Massachusetts Amherst neuroscientist Gerald Downes and colleagues have developed just such a model, a mutant zebrafish, to study Maple Syrup Urine Disease (MSUD). It is an inherited metabolic disorder that causes affected individuals to smell like maple syrup. Untreated, it can result in mental retardation, profound neurological damage, severe dystonia, coma and death. This new model is described in an early online version of the March issue of the journal Disease Models and Mechanisms.

A mouse model does exist and has been useful to provide new insight into the disorder, Downes says, but mouse studies can be expensive and time-consuming. Many of the cellular and molecular mechanisms that promote brain injury in MSUD are not known, and new platforms are needed to better understand how this disease causes brain injury and to develop new therapies. MSUD affects about one in every 185,000 children but the rate of incidence can be about 10 times higher in certain religious communities.

Downes, who leads a research team using zebrafish to investigate human neurological disorders, explains that MSUD causes disease by disrupting the proper metabolic breakdown of three amino acids: Isoleucine, leucine and valine, found in protein-rich foods such as eggs, meat and milk. These amino acids and their by-products accumulate to toxic levels in the body, with devastating effects on the brain and nervous system. A major symptom is severe dystonia, a neurological condition that results in twisting, abnormal postures due to sustained muscle contractions.

As part of this study supported by the National Institute of Neurobiological Disorders and Stroke at the National Institutes of Health, Downes and doctoral student Timo Friedrich examined a zebrafish mutant named questschkommode, or que that exhibits abnormal swimming behavior. They analyzed high-speed video of larval zebrafish swimming in response to a light touch and found that que mutants perform what is called "accordion behavior."

Instead of normal swimming with left and right tail flips, the mutant que fish compress like an accordion along the nose-to-tail axis (questschkommode means "squeezebox" in German). This behavior is believed to be similar to the dystonia MSUD-affected human patients display during periods of severe metabolic distress.

Collaborating with Aaron Lambert and Mark Masino at the University of Minnesota to record and measure nerve activity, the UMass Amherst researchers further confirmed that dystonia in the que mutant originates in the brain and spinal cord, not in muscle, indicating that the nervous system functions abnormally.

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  1. Melinda M Melinda M United States says:

    Thanks so much for all you do.  I am so sorry to hear we will be unable to attend the symposium this year, would be great to hear more from you and your colleagues. It keeps that small hope alive that one day my son could be cured. Though he has fared better than some of the other MSUD patients, I am sure it will still be a large relief for him and us to have one less burden and worrry, especially in today's world.  It is also amazing how much we learn from other creatures and develop answers to other problems from another.

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