Researchers have shown how faults in DNA repair, caused by gene mutations, can lead to motor neurone disease, pointing to possible new treatment targets.
The study found that mutations in the CFAP410 gene make neurones more vulnerable to DNA damage, rather than disrupting cell structures as once believed.
Motor neurone disease (MND), also called amyotrophic lateral sclerosis (ALS), causes the progressive loss of nerve cells that control muscles, affecting 3–5 people per 100,000 worldwide.
Scientists from the University of Bath’s department of life sciences used gene editing in mouse embryonic stem cells to study two CFAP410 mutations commonly seen in MND patients.
The CFAP410 protein is found in cilia – tiny hair-like projections on cell surfaces – and helps protect cells against DNA damage. Earlier research suggested faulty CFAP410 disrupted cilia formation.
But the Bath team found that cilia remained intact in neurones with the mutated gene.
Instead, the mutations altered how CFAP410 interacts with a protein called Nek1, which triggers the cell’s DNA repair system.
This made motor neurone cells less able to fix DNA damage and more sensitive to chemical stress, leading to higher cell death.
Dr Vasanta Subramanian, reader in Bath’s department of life sciences, 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 highlight potential targets for new therapies.”
The team generated neurones from stem cells and tested their response to chemical stress that causes DNA damage.
Cells with the mutated gene were less able to repair damage and showed increased death rates.
The researchers say the results suggest DNA repair failure is the key driver of MND in these cases, rather than defects in cilia.
They now plan to investigate the molecular mechanisms further to help guide drug development.
Dr Subramanian added: “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.”
