Researchers at the University of Bath have discovered how DNA damage caused by a faulty DNA protection and repair system can lead to neurodegenerative disorders such as Motor Neurone Disease (MND).
Motor Neurone Disease, also known as Amyotrophic Lateral Sclerosis (ALS), is a terminal neurodegenerative disease which causes progressive loss of the neurones that control the muscles.
It affects 3-5 people per 100,000 worldwide and is on the rise. Its exact cause is unknown, however several faulty genes have been linked to MND, including mutations of the gene that codes for a protein called CFAP410.
The full functions of this protein are not well understood, but it is found in tiny finger-like structures on the surface of some cells called cilia, which are involved in many cell functions including signalling pathways crucial for brain development. CFAP410 is also involved in protecting the cell from, and repairing, DNA damage.
The researchers, from the University of Bath's Department of Life Sciences, used gene editing techniques in mouse embryonic stem cells to investigate the effects of two mutations of CFAP410 commonly found in patients with MND.
After introducing the mutated gene, the researchers induced the cells to make neurones and observed the effects on cilia formation and the response of the cells to chemical stress leading to DNA damage.
Previous work by others has shown that knocking out the CFAP410 gene harms cilia formation, however the Bath researchers found that cilia were unaffected in neurones edited to contain the mutated gene.
Instead, they found that the mutations in CFAP410 changed the protein's interaction with another protein called Nek1, which activates the cell's DNA repair system. This resulted in the motor neurone cells being more susceptible to DNA damage.
These cells were less able to repair the damage and were more sensitive to various chemical stressors, leading to higher rates of cell death.
Publishing in the journal iScience , the authors say their findings suggest it is this DNA damage that is likely to cause MND.
Dr Vasanta Subramanian , Reader in the University's Department of Life Sciences who led the research, said: "MND is a devastating illness that currently has no cure, and is on the rise globally.
"Whilst CFAP410 has been linked with MND previously, we've used gene editing for the first time to show that mutations in this gene contribute to the disease by making cells more vulnerable to DNA damage and stress, ultimately leading to death of the motor neurones.
"Our findings identify new insights into the mechanisms underlying MND and highlights potential targets for new therapies."
The researchers will next focus on understanding the molecular mechanism of MND in more detail with a view to developing targeted therapeutics.
Dr Subramanian said: "Since our findings show that mutations in CFAP410 lead to increased DNA damage and faulty repair mechanisms, we hope that new therapies that could enhance DNA repair or protect against DNA damage could be one avenue to explore for treating the disease."
