Study sheds light on underlying causes of impaired brain function in muscular dystrophy

August 8, 2012
The red dots are the toxic RNAs accumulating in the nucleus (blue) of a myotonic dystrophy cell (these are induced pluripotent stem, or iPS, cells) and the green is a neuronal marker. Credit: Charizanis et al., Neuron.

University of Florida researchers have identified a gene responsible for brain-related symptoms of the most common form of adult-onset muscular dystrophy.

Disruption in the gene’s function is linked to memory loss, learning difficulties and extreme daytime sleepiness. The gene produces a brain protein previously thought to be of no importance in the disease myotonic dystrophy, which causes muscle weakness and disturbs electrical signals in the heart.

The findings appear Aug. 8 in the journal Neuron.

“Now we understand one of the major events that occurs in the brain of someone with myotonic dystrophy,” said senior author Maurice Swanson, a professor of molecular genetics and microbiology and a member of the UF Genetics Institute. “We know that the same patterns of gene expression activity that occur in skeletal muscle and the heart are also happening in the brain, and we have a disease model that we can study to understand more.”

Myotonic dystrophy usually strikes people in their 20s or 30s, causing increased muscle loss over time. Other symptoms include impaired brain function and sleep difficulties. The disease, which can be life-threatening, affects about one in 8,000 people in the general population, according to the National Institutes of Health.

The disease is caused when a section of DNA repeats excessively. As a result, the genetic material responsible for copying that DNA pattern and serving as a blueprint for protein production can be up to 450 times longer than normal. The abnormal repeated sections of genetic material become longer and longer in succeeding generations, causing the disease to become worse and worse from generation to generation.

Patients start getting muscle symptoms when the extra-long pieces of protein blueprint, called messenger RNA, loop back on themselves, forming hairpin-like structures that bind to and disrupt the function of a key protein called muscleblind-like protein 1. That protein controls a process called splicing, in which chunks of the RNA are cut and rejoined in differing patterns to produce the variety of proteins needed for development. By hindering this process, the abnormal RNA prevents the conversion of fetal muscle to adult muscle as people age.

But Swanson and colleagues were unsure what related processes occurred in the brain. They started investigating the cause of brain-related symptoms after talking with patients, who explained that those issues were of most immediate concern.

“We were surprised, because we realized we weren’t attacking a major problem that concerned people affected by this disease,” Swanson said.

To try to unravel the mystery of how the disease works in the brain, Swanson and colleagues looked to a brain protein similar to the one responsible for the disease symptoms in muscle. They studied both behavioral and molecular-level changes in mice lacking the gene that produces a protein called muscleblind-like protein 2, which is analogous to the muscleblind-like protein 1 that causes muscle symptoms in humans.

Without the protein, the mice developed several of the brain-based symptoms that occur in patients who have myotonic dystrophy. On the molecular level, the mice had abnormal levels of brain chemicals that help to regulate thought processes. In addition, the connections between nerve cells in the brain’s memory center did not respond well to changes in stimuli.

The researchers found for the first time that, underlying those conditions, at hundreds of points within the genetic blueprint there was disruption of the cutting and rejoining process that creates protein variety. Together, the findings suggest that the brain-related symptoms of myotonic dystrophy result from disruptions in the function of the gene that produces muscleblind-like protein 2.

“This is really new information,” said Dr. Thomas Cooper, the S. Donald Greenberg professor of pathology and professor of molecular and cellular biology at Baylor College of Medicine, who was not involved in the study. “Before, this gene was thought not to be so important, so in people’s minds it was put on the back burner. This study showed that if you do a good analysis you can find that it is very important in the brain.”

Explore further: Antisense oligonucleotides make sense in myotonic dystrophy

More information: Charizanis et al.: "Muscleblind-Like 2 Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy." Neuron, DOI:10.1016/j.neuron.2012.05.029

Related Stories

Antisense oligonucleotides make sense in myotonic dystrophy

February 27, 2012
Antisense oligonucleotides – short segments of genetic material designed to target specific areas of a gene or chromosome – that activated an enzyme to "chew up" toxic RNA (ribonucleic acid) could point the way ...

Some muscular dystrophy patients at increased risk for cancer

December 13, 2011
People who have the most common type of adult muscular dystrophy also have a higher risk of getting cancer, according to a paper published today in the Journal of the American Medical Association.

Recommended for you

Research redefines proteins' role in the development of spinal sensory cells

September 19, 2017
A recent study led by Samantha Butler at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA has overturned a common belief about how a certain class of proteins in the spinal cord regulate ...

Team discovers how to train damaging inflammatory cells to promote repair after stroke

September 19, 2017
White blood cells called neutrophils are like soldiers in your body that form in the bone marrow and at the first sign of microbial attack, head for the site of injury just as fast as they can to neutralize invading bacteria ...

The brain at work: Spotting half-hidden objects

September 19, 2017
How does a driver's brain realize that a stop sign is behind a bush when only a red edge is showing? Or how can a monkey suspect that the yellow sliver in the leaves is a round piece of fruit?

Epileptic seizures show long-distance effects

September 19, 2017
The area in which an epileptic seizure starts in the brain, may be small but it reaches other parts of the brain at distances of over ten centimeters. That distant activity, in turn, influences the epileptic core, according ...

Study uncovers markers for severe form of multiple sclerosis

September 18, 2017
Scientists have uncovered two closely related cytokines—molecules involved in cell communication and movement—that may explain why some people develop progressive multiple sclerosis (MS), the most severe form of the disease. ...

Genetically altered mice bear some hallmarks of human bipolar behavior

September 18, 2017
Johns Hopkins researchers report they have genetically engineered mice that display many of the behavioral hallmarks of human bipolar disorder, and that the abnormal behaviors the rodents show can be reversed using well-established ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.