What are the aims of this research project?
When a gene is switched on, RNA copies of the gene are produced within the cell nucleus. This RNA acts as a messenger that travels out of the nucleus and into the cytoplasm, where it instructs the cell’s machinery to make proteins.
In myotonic dystrophy type 1, this RNA production process is disrupted. Mutations in the DMPK gene result in the production of faulty RNA copies, which become trapped in clumps in the nucleus.
The trapped DMPK RNA binds to a protein called MBNL1. This prevents MBNL1 from regulating the activity of other genes, which is thought to lead to symptoms of myotonic dystrophy type 1.
Dr Sleeman and her team recently showed that MBNL1 is normally located in structures within the nucleus called paraspeckles. However, in cells from people with myotonic dystrophy type 1, less MBNL1 is found in paraspeckles, which may be because it is found in the clumps of trapped DMPK RNA instead.
The primary aim of this project is to gain a better understanding of the changes within the nucleus that lead to myotonic dystrophy type 1. Dr Sleeman and her team will further investigate the relationship between paraspeckles and MBNL1 protein by studying cells from people with myotonic dystrophy type 1 and comparing them to healthy control cells. They will also assess how the clumps of DMPK RNA interact with MBNL1 protein in cells from people with myotonic dystrophy type 1.
Why is this research important?
It is not understood how the clumps of DMPK RNA cause myotonic dystrophy type 1. Accumulation of MBNL1 protein in them is thought to be involved but it is not clear how. This research will fill in some of these blanks and give a better understanding of what is going wrong inside the cells of people with myotonic dystrophy type 1. This will help to direct future research into potential treatments.
How will the outcomes of this research benefit people with myotonic dystrophy?
A more complete understanding of how the nucleus controls RNA production and how this goes wrong in myotonic dystrophy type 1 will enable researchers to design novel therapeutic strategies. For example, it may be possible to prevent MBNL1 accumulation in the clumps of DMPK RNA and destroy the clumps by manipulating structures within the nucleus.
How might this research impact on other neuromuscular conditions?
RNA production is not only disrupted in myotonic dystrophy type 1, but also in other degenerative conditions, including spinal muscular atrophy (SMA). Therefore the findings of this research could also help to improve the biological understanding of SMA.
Grant information
Project leader: Dr Judith Sleeman
Institute: University of St Andrews
Condition: Myotonic dystrophy type 1
Duration: three years, starting 2016
Total cost: £174,803
Official title: Involvement of the paraspeckle nuclear domain in myotonic dystrophy type 1
Further information
Find out what other myotonic dystrophy research projects we’re funding
Read our factsheet on myotonic dystrophy
It is only through your contributions that we can continue to fund the vital work that takes us closer to finding treatments for muscle-wasting conditions. Donate now and help change the lives of thousands of people living with these conditions. Thank you for your support.