New knowledge about muscular dystrophy

May 5, 2014
Cells isolated from muscular dystrophy patients are stained for the toxic RNA (red), which is often seen in the cell nucleus (marked blue). Credit: Christian Damgaard

Researchers at Aarhus University have revealed a previously unknown function of a cellular enzyme that can disperse toxic aggregates in the cells of patients with muscular dystrophy.

The most common form of muscular dystrophy among adults is dystrophia myotonica type 1 (DM1), where approximately 1 in every 8000 is affected by the disease. The severity of the disease varies from mild forms to severe congenital forms. It is dominantly inherited and accumulates through generations, gaining increased severity and lowered age of onset. DM1 is characterised by accumulating toxic aggregates of ribonucleic acids (RNA) from a specific mutated gene (see figure 1).

When this RNA, which contains thousands of CUG nucleotide repeats, builds up in the cell, it attracts several cellular proteins, including muscleblind 1 (MBNL1) (see figure 2, left). This binding inhibits the normal function of MBNL1, which means that the cellular level of a number of specific proteins becomes deregulated and the disease develops.

Enzyme characterisation in muscular dystrophy patients

The researchers work at the Department of Molecular Biology and Genetics and the Department of Biomedicine, Aarhus University, where they characterised an called DDX6, found in both normal and cells from muscular dystrophy patients.

The enzyme constantly tries to disperse the toxic aggregates and release MBNL1 in cells from muscular dystrophy patients, which means that the protein can carry out its normal function (see figure 2, right). The enzyme is found in many different cell types, where it performs a number of vital functions. The researchers showed that an artificial increase in the level of DDX6 in muscular dystrophy cells reduces the number of RNA aggregates, while more are formed when DDX6 is removed from the cells.

Left: The toxic RNA in DM1 cells consists of a number of CUG triplets that are often repeated thousands of times, forming a specific structure as shown. The MBNL1 protein binds to this structure, thus failing to carry out its normal function in the cell. The expression of a number of genes becomes deregulated in the cell and the disease occurs. Right: DDX6 can "unwind" the structure with its enzyme activity and MBNL1 leaves the complex to carry out its normal functions in the cell. Credit: Christian Damgaard

DDX6 belongs to a class of enzymes called helicases, which can change RNA structure and also regulate the ability of proteins to bind RNA. By purifying DDX6 from human cells, the researchers succeeded in getting the enzyme to bind and carry out an enzymatic reaction outside the cell, thus changing the structure of the toxic RNA.

These results indicate that DDX6 has a direct impact on toxic RNA aggregation in cells from muscular dystrophy patients in addition to its normal functions.

It remains unlikely that DDX6 can be used directly in the treatment of , since the enzyme carries out a number of important processes in the cell, which could potentially become deregulated leading to other diseases. However, the results provide important insights into the basic mechanisms of the disease, and natural differences in enzyme levels in different types of cells (or individuals) could possibly explain observed tissue-specific differences in the development of the disease.

Explore further: Scientists uncover image of muscular dystrophy defect and design targeted drug candidates

More information: Nucleic Acids Research: DDX6 regulates sequestered nuclear CUG-expanded DMPK-mRNA in dystrophia myotonica type 1: nar.oxfordjournals.org/content … 5/03/nar.gku352.full

Related Stories

Scientists uncover image of muscular dystrophy defect and design targeted drug candidates

January 2, 2014
Scientists from the Florida campus of The Scripps Research Institute have revealed an atomic-level view of a genetic defect that causes a form of muscular dystrophy, myotonic dystrophy type 2, and have used this information ...

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 ...

Aberrant splicing saps the strength of 'slow' muscle fibers

July 29, 2013
When you sprint, the "fast" muscle fibers give you that winning kick. In a marathon or just day-to-day activity, however, the "slow," or type 1 fibers, keep you going for hours.

New muscular dystrophy drug's chances for approval improve

April 22, 2014
(HealthDay)—A new drug to treat Duchenne muscular dystrophy may be closer to becoming the first approved treatment for the disease.

Scientists turn muscular dystrophy defect on and off in cells

June 28, 2013
For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified small molecules that allow for complete control over a genetic defect responsible for the most common adult onset ...

Recommended for you

Team finds link between backup immune defense, mutation seen in Crohn's disease

July 27, 2017
Genes that regulate a cellular recycling system called autophagy are commonly mutated in Crohn's disease patients, though the link between biological housekeeping and inflammatory bowel disease remained a mystery. Now, researchers ...

Study finds harmful protein on acid triggers a life-threatening disease

July 27, 2017
Using an array of modern biochemical and structural biology techniques, researchers from Boston University School of Medicine (BUSM) have begun to unravel the mystery of how acidity influences a small protein called serum ...

CRISPR sheds light on rare pediatric bone marrow failure syndrome

July 27, 2017
Using the gene editing technology CRISPR, scientists have shed light on a rare, sometimes fatal syndrome that causes children to gradually lose the ability to manufacture vital blood cells.

Post-stroke patients reach terra firma with new exosuit technology

July 26, 2017
Upright walking on two legs is a defining trait in humans, enabling them to move very efficiently throughout their environment. This can all change in the blink of an eye when a stroke occurs. In about 80% of patients post-stroke, ...

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

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.