While remarkable, this active transcription does not come without a cost. Instead, it ultimately makes DNA more vulnerable to breaks– essentially damaging the critical instructions necessary to create key proteins for cellular function.
“There’s this contradiction there on a biological level– neuronal activity is critical to neuron performance and survival, yet inherently damaging to the DNA of the cells,” detailed Daniel Gilliam, the study’s co-first author.
This pushed the researchers to become intrigued with the brain’s balance of pros and cons. They wondered if the neurons employed specific mechanisms to alleviate the damage– allowing people to think, remember, and learn throughout many decades of life.
So, the team focused on the transcription factor NPAS4, which was discovered in 2008 by Michael Greenberg’s lab. This protein, which is highly specific to neurons, regulates activity-dependent gene expression to manage inhibition in excitatory neurons while they react to external stimuli.
“NPAS4 is primarily turned on in neurons in response to elevate neuronal activity that’s driven by changes in sensory experience, and so we wanted to understand the functions of this factor,” Pollina noted.
This led the researchers to conduct various biochemical and genomic experiments using mice in their latest study. First, they found that NPAS4 is part of a protein complex made up of 21 different proteins– otherwise known as NPAS4–NuA4.
Afterward, the team confirmed that the complex binds to neuronal DNA sites with significant damage. They also mapped out the locations of these sites.
The researchers revealed how more DNA breaks occurred when components of the protein complex were inactivated. At the same time, there was lower recruitment of repair factors.
Additionally, at sites where the complex was present, mutations accumulated slower as opposed to sites without the complex. And finally, the researchers found that mice without the NPAS4–NuA4 complex in their neurons had drastically shorter life spans.
“What we found is that this factor plays a critical role in initiating a novel DNA repair pathway that can prevent the breaks that occur alongside transcription in activated neurons,” Pollina explained.
“It’s this extra layer of DNA maintenance that’s embedded within the neuronal response to activity. It provides a potential solution to the problem that you need a certain amount of activity to sustain neuronal health and longevity, but the activity itself is damaging,” added Gilliam.