Turning Myotonic Dystrophy On and Off in Cells

MDA grantee Matthew Disney is a current and former MDA grantee at the Scripps Research Institute in Jupiter, Fla. Disney's current MDA grant is focused on targeting toxic RNA in type 2 myotonic dystrophy (MMD2, or DM2).

A team of scientists led by MDA grantee Matthew Disney at the Scripps Research Institute in Jupiter, Fla., has identified two small molecules that they say will be extremely useful in understanding type 1 myotonic muscular dystrophy (MMD1, or DM1) and testing experimental therapies for this disorder in the laboratory.

Compound 1 causes normal cells to behave like MMD1-affected cells, while compound 2 reverses the process, making MMD1-affected cells act like normal cells. (Even though it reverses MMD1 effects in cells, compound 2 is not slated for development as a treatment. Disney says it's a good tool for measuring long-term changes in cells but "nowhere near as potent" as other compounds he is working on, which are in development as potential treatments.)

Disney and colleagues reported their findings online June 28, 2013 in Nature Communications.

Abnormal 'splicing' is MMD1 hallmark

MMD1 is caused by an abnormally expanded DMPK gene. When the DMPK DNA is longer than normal, it causes a longer-than-normal RNA strand to be produced, consisting of repeated chemical sequences known as CUG (cytosine, uracil, guanine).

The overly long RNA can contain hundreds or even thousands of times the number of repeated CUG sequences (CUG "repeats") seen in cells not affected by the MMD1 mutation. The expanded RNA acts like a web, trapping important proteins and keeping them from their usual cellular jobs.

One crucial protein that ends up hopelessly ensnared in the CUG strands is called MBNL1. MBNL1's usual job is to ensure that several other proteins — including some controlling the actions of insulin, the movement of chloride ions and some aspects of cardiac function — are properly made. The part of the protein-making process that MBNL1 influences is called RNA splicing.

RNA splicing abnormalities are a crucial part of the MMD1 disease process, although they probably aren't the only abnormalities responsible for the disease.

One challenge for scientists to date has been that they haven't been able to "turn off" the splicing abnormalities to see what else might be going wrong in MMD1-affected cells.

Two 'hits' from chemical screen

The study was initiated when Charles Thornton at the University of Rochester (N.Y.) and researchers at the National Institutes of Health in Bethesda, Md., screened a chemical library for small molecules that would interact with either the CUG repeats or the MBNL1 protein. (Thornton has a current MDA research grant for related MMD1 research and is an author on the current study.)

Disney and his colleagues analyzed data from this screen and came up with two "hits."

Compound 1, the researchers found, causes the same splicing defects that are seen in MMD1-affected cells. The compound sticks to the MBNL1 protein, keeping it from interacting with the CUG repeats but also inactivating it.

Compound 2, on the other hand, markedly improves the splicing of proteins in cells carrying an MMD1-causing mutation. Compound 2 sticks strictly to the CUG repeats, freeing the MBNL1 protein to perform its usual roles.

This approach to using small molecules to induce or reverse a disease is "unprecedented," Disney said.

For one thing, he noted, the findings have shown that targeting MBNL1 is not a good strategy for treating MMD1.

Another result of the findings, he says, is that researchers can now use the new molecules to turn off abnormal RNA splicing and see what abnormalities remain in MMD1-affected cells.

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