TDP-43 and alternative splicing in motor neurone disease

Description:

MRC/MND Association Lady Edith Wolfson Fellowship

About Dr Highley:

“My first degree was in psychology at the University of Oxford, where I subsequently researched brain changes in schizophrenia for my PhD. Having decided on a career as a neuropathologist (a doctor who specialises in the microscopic study of diseased brain and spinal cord), I did a medical degree in Birmingham and then moved to Sheffield for specialist training.

“I met Professors Paul Ince and Pamela Shaw when I arrived in Sheffield five years ago and they introduced me to their world-class research into MND. I developed an interest in this condition, and performed a small amount of research in my spare time. Receiving the MRC/MND Association Lady Edith Wolfson Clinician Scientist Fellowship gives me the time and resources to work on MND on a formal footing and to gather some really important data.

“Sheffield is a centre of international excellence for MND research. I am enormously looking forward to working in this vibrant environment, and am immensely grateful to the MND Association and the MRC for funding this project.”

What this research means to you:

Dr Highley’s project will concern a protein called TDP-43. In healthy neurones, TDP-43 is located in a compartment of the cell called the nucleus – where the cell’s genes are stored. However, a recent discovery has revealed that in diseased motor neurones, TDP-43 is not present in the nucleus. Instead it is deposited in the cell outside the nucleus and for some reason it is labelled for destruction. Following this discovery, TDP-43 has become an exciting field of MND research. The question Dr Highley will address is: “What does TDP-43 do in normal cells that it is not doing in diseased motor neurones?”

Dr Highley explains in more detail:

“Genes contain instructions that tell cells how to manufacture proteins. TDP-43 is known to be involved in a process whereby the instructions for specific proteins are modified to produce different versions of the same proteins. This is a process called ‘alternative splicing’. If TDP-43 is not working properly the wrong versions of proteins will be manufactured, causing the cell to malfunction in some way.

“I will study spinal cord tissue that has been very kindly donated to research by people who have died with MND. I will use laser technology to dissect both diseased and surviving healthy motor neurones. In addition, I will grow some motor neurone-like cells and use a specially adapted virus to disrupt the production of TDP-43 in some of these cells to mimic the effects of MND. I will compare alternative splicing in the diseased and healthy motor neurones from the spinal cords and from the laboratory-grown cells.

“The project will hopefully generate data about the chain of events that causes a motor neurone to die. Such knowledge may be used to develop drugs designed to interrupt this process and allow motor neurones to survive, and thereby either slow or, ideally, stop the disease progression.”