The molecular missteps that disrupt brain function in the most common form of adult-onset muscular dystrophy have been revealed in a new study published by Cell Press. Myotonic dystrophy is marked by progressive muscle wasting and weakness, as well as excessive daytime sleepiness, memory problems, and mental retardation. A new mouse model reported in the August 9 issue of the journal Neuron reproduces key cognitive and behavioral symptoms of this disease and could be used to develop drug treatments, which are currently lacking.
"The new animal model reproduces important aspects of myotonic dystrophy brain disease, so this model may be useful to develop biomarkers and test future drug therapies," says senior study author Maurice Swanson of the University of Florida.
Previous studies had shown that mutated genes underlying the disease produce toxic ribonucleic acids (RNAs) during transcription, and these RNAs cause the production of incorrect forms of proteins in muscle tissue by blocking the actions of a protein called MBNL1. As a result, proteins typically found in fetal muscles increase in abundance, while the normal suite of proteins found in adult muscles decrease in number. However, until now, it was not clear whether molecular abnormalities similar to those in muscle tissue of individuals with mytonic dystrophy also occur in the brain, resulting in the cognitive neurological problems.
In the new study, Swanson and his team focused on a related protein called MBNL2, which is found in the brain. They developed a new mouse model that lacked a functional Mbnl2 gene. These animals experienced an increase in the amount of rapid eye movement sleep as well as learning and memory deficits, similar to human patients.
The researchers also found extensive evidence of toxic RNAs in the hippocampus, as well as signs that fetal proteins were being produced in the brains of adult mutants. This pattern was also evident in the autopsied brain tissue of humans who had myotonic dystrophy. "This study should accelerate our understanding of how myotonic dystrophy mutations impact brain development and function," Swanson says.
Charizanis et al.: "Muscleblind-Like 2 Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy."