Neuroscientists and cancer researchers at the Francis Crick Institute and UCL have teamed up to explore whether DNA damage contributes to the development or progression of motor neurone disease.
Motor neurone disease (MND) is a rare condition affecting the motor nerve cells. MND affects up to 5,000 adults in the UK at any one time and causes a range of challenging symptoms, such as muscle weakness or speech and communication problems. At the moment, MND is untreatable and the underlying causes are not understood.
Taking learnings from cancer into the MND field
When DNA is replicated in every cell in our body, errors can occur, but we have processes to repair the damage. Occasionally, these repair mechanisms malfunction, which can lead to mutations, instability in our genes and cancer.
The DSB Repair Metabolism Laboratory at the Crick, led by Simon Boulton, aims to find out how cells repair damage to DNA and how failures in this process can lead to disease. The lab is now applying this expertise to a new challenge: could DNA damage contribute to MND?
Simon and team will work with the Human Stem Cells and Neurodegeneration Laboratory at the Crick and UCL, led by Rickie Patani. Rickie’s lab uses stem cells from MND patients to understand how MND develops. If the researchers find that DNA damage is an important contributor to MND, they hope to unravel the biological processes behind this and identify targets for future treatments.
What’s the link between DNA damage, RNA processing and MND?
One of the most common hallmarks of MND is malfunction of a protein called TDP-43, which is known as an RNA binding protein. It regulates which genes the cell turns on and off.
Led by Giulia Tyzack, senior research fellow in Rickie Patani’s lab together with Nishita Parnandi, postdoctoral research fellow in Simon Boulton’s lab, the research team will explore the idea that losing the function of RNA binding proteins like TDP-43 causes instability in DNA.
They will look into ‘R-loop formation’ - how loss of specific RNA binding protein function could render one DNA strand exposed and vulnerable to damage. They will also look at how RNA can be cut in the wrong places if specific RNA binding proteins such as TDP-43 are not present.
The resulting DNA instability from these processes could lead to further loss of RNA binding proteins, causing a vicious cycle which ultimately means motor nerve cells die.
How will the team test this theory?
The researchers will use stem cells taken from the skin of people with MND to make motor nerve cells. They will then sequence the DNA and RNA and image the cells, to understand the nature and sequence of any DNA instability and damage.
They will then look at mice with MND as well as spinal cord tissue taken from people who have died from MND, to see if the same processes happen. Ultimately this work could pave the way for new therapies to prevent DNA instability.
Dr Giulia Tyzack, senior research fellow in the Human Stem Cells and Regeneration Laboratory at the Crick and UCL, and leader of the study, said: “We are very excited to start working on this project which will allow us to unravel the fundamental disease mechanisms underlying MND. We believe that combining our lab’s knowledge of MND models and RNA biology together with the Boulton lab’s world-leading expertise in the DNA damage field, we are optimally poised to make impactful discoveries for MND therapy.”
Dr Nishita Parnandi, a postdoctoral research fellow in the DSB Repair Metabolism Laboratory at the Crick, said: “We are excited to combine our expertise and complementary skill sets in driving this project forward. We expect to gain valuable insights into mechanisms of genome instability in people with MND."
Jessica Lee, Director of Research at My Name’5 Doddie Foundation, said “We are committed to funding research that will accelerate the development of new treatments for MND; a devastating condition which currently has no effective treatments. The exciting and potentially ground-breaking nature of this project is reflected in the significant investment we are making. When we launched our new research strategy, Catalysing a Cure, this kind of project, with the potential to open up new therapeutic avenues, was exactly what we had in mind.”