In a recent study, published in Nature, researchers from Harvard Medical School have identified a novel DNA damage repair pathway, found exclusively in neurons. The work sheds light on a long-standing question as to how these cells survive for extended periods of time in the brain.
Contradicting signals
Neurons are some of the most vital cells in the body. Using electrical signals, these cells are responsible for passing messages throughout the body, from the nervous system to the brain. Unlike most other cell types, neurons typically do not replicate, instead remodelling themselves to adapt to different stimuli in response to signals from activity-induced promoters. However, the process of remodelling in response to activity leaves neuronal DNA susceptible to damage, more so than other cell types. This type of damage is characteristic of many neurodegenerative disorders. An issue described as a “contradiction on a biological level” by author Daniel Gilliam, the question remains as to how neurons can generally persist across a lifetime if their own function leaves them vulnerable to damage.
Michael Greenberg and his team from Harvard Medical School set out to address this question, carrying out experiments in mice to identify neuron-specific DNA repair mechanisms.
A novel repair mechanism
The transcription factor NPAS4 has long been known to act specifically in neuronal cells. The team purified NPAS4, derived from the brains of adult mice, in order to determine if the protein acts as part of a complex. Using a variety of techniques including size exclusion chromatography and mass spectrometry, they discovered that NPAS4 interacts with the NuA4 complex – a chromatin modifier that is known to be involved in the repair of double-strand breaks.
Given this information, and to further determine the role of the NPAS4-NuA4 complex in neurons, the researchers investigated the response to severe DNA damage. They found that the NPAS4-NuA4 complex is recruited to areas prone to double-strand breaks following neuronal stimulation, often close to activity-induced promoters. They observed that these areas undergo DNA repair following the enhanced recruitment of repair factors to the site.
The above was further proven by subsequent experiments in which the NPAS4-NuA4 complex was impaired. Following depletion of the NPAS4 transcription factor, double-strand breaks were not repaired as efficiently, and occurred at a higher rate – implying that the NPAS4-NuA4 complex also acts as a protective agent.
Figure 1. Image showing the pathway from activity to DNA repair in neuronal cells. ARNT2 is found in complex with NPAS4 whilst TIP60 is part of the NuA4 complex. Adapted from Pollina et al., 2023.
An age-old question
Ultimately, the team discovered that impairment of the NPAS4-NuA4 complex led to decreased life expectancy in mice. This was perhaps to be expected, given that neuronal genome instability is correlated with ageing across many organisms. Knowledge of the processes governing the longevity of neurons is therefore critical in our understanding of cognitive and neurodegenerative diseases.
Whilst the work was only carried out in mice, the NPAS4-NuA4 complex is conserved in humans, and as such, more work is needed to confirm that the findings of this study translate to the human brain. The team have a variety of ideas of what to ask next, including the intriguing question of whether this DNA repair pathway operates differently in species with varying lifespans. Greenberg stated: “It may turn out that this mechanism is even more prevalent in the human brain, where you have so much more time for these breaks to occur and for DNA to be repaired.”
