How DNA Damage Contributes to the Development of Motor Neuron Disease

Researchers at the University of Bath have uncovered a crucial link between DNA damage caused by faulty DNA protection and repair mechanisms and the onset of neurodegenerative disorders such as motor neuron disease (MND). This disease, often associated with a form of amyotrophic lateral sclerosis (ALS), is characterized by the progressive loss of motor neurons, leading to muscle weakness and eventual paralysis. MND affects approximately 3 to 5 individuals per 100,000 globally and has been increasing in prevalence. Despite extensive research, the precise causes of MND remain unclear.

Genetic studies have identified several faulty genes associated with MND, including mutations in the gene encoding the protein CFAP410. This protein resides in tiny, finger-like projections called cilia on cell surfaces, which are essential for various cellular functions such as signaling pathways vital for brain development. Additionally, CFAP410 plays a role in protecting cells from DNA damage and facilitating repair.

In their study, scientists utilized gene editing techniques in mouse embryonic stem cells to investigate the effects of two common CFAP410 mutations identified in MND patients. They induced neuronal differentiation and observed the impact of these mutations on cilia formation and the cellular response to chemical stress that causes DNA damage.

Previous research had suggested that knocking out CFAP410 impairs cilia formation; however, this study found that in neurons with mutated CFAP410, cilia remained unaffected. Instead, mutations altered how CFAP410 interacts with another protein called Nek1, which activates the DNA repair system. This interaction was compromised, rendering motor neurons more vulnerable to DNA damage.

The impaired interaction resulted in reduced DNA repair efficiency, making the neurons more susceptible to stress and increasing their likelihood of death. These findings suggest that cellular sensitivity to DNA damage and the inability to repair it effectively may be central to the development of MND.

The study, published in iScience, indicates that DNA damage and faulty repair mechanisms are potential primary drivers of MND pathogenesis. Dr. Vasanta Subramanian, the research lead, emphasizes that while CFAP410 mutations have been associated with MND before, their work provides direct evidence that such mutations contribute to disease progression by weakening cellular defenses against DNA damage.

Looking forward, the researchers plan to explore the molecular mechanisms involved more deeply to identify targeted therapeutic strategies. By understanding how mutations lead to increased DNA damage susceptibility, they hope to develop treatments that enhance DNA repair or protect neurons from damage—potentially slowing or halting the progression of MND.

This research offers promising new insights into the pathogenesis of motor neuron disease and opens avenues for novel treatment options aimed at bolstering cellular resilience to DNA damage.