As we age, the saying “Use it or lose it” is often applied broadly to include not only our muscles, but also our minds. This means that if we do not engage in regular physical or mental activity, we may experience a decline in our abilities over time.

While it’s true that using our brain cells can help preserve our memory and cognitive abilities as we age, it’s not entirely a positive thing. Recent research has shown that increased brain activity can actually cause damage to neurons by creating breaks in their DNA.

This begs the question, how can neurons stay healthy and effective after carrying out their crucial activity in the brain for a lifetime?

Now, researchers at Harvard Medical School have discovered a unique DNA repair process that only happens in neurons, which are the body’s longest-living cells. The study, tested in mice and published in Nature today, helps to explain why neurons continue to operate over time despite heavy repeated effort.

The results demonstrate that a protein complex termed NPAS4-NuA4 activates a mechanism to repair DNA damages caused by neuronal activity.

Well more research is needed, Elizabeth Pollina, co-first author and assistant professor of developmental biology at the Washington University School of Medicine, who conducted the research while a research fellow at HMS, says, “this is a really promising mechanism to explain how neurons maintain their longevity over time.”

If the results are verified in other animal experiments and eventually in people, they might help scientists in understanding the exact mechanism by which neurons in the brain degrade with age or due to neurodegenerative illnesses.

Neurons are unique among the many different cell types in the body because they do not reproduce or renew like most other cell types. They relentlessly strive to restructure themselves in response to environmental signals day in and day out, year in and year out, ensuring that the brain can adapt and function across a lifetime.

The brain’s new transcriptional programs are partially responsible for this remodeling process. These programs enable neurons to translate DNA into instructions for building proteins. However, vigorous transcription in neurons has a significant cost: it makes DNA more brittle, destroying the genetic instructions required to produce proteins that are so crucial for cellular function.

According to co-first author Daniel Gilliam, a graduate student in the Program in Neuroscience at HMS, there is this “contradiction there on a biological level” — neural activity is necessary to neuron efficiency and survival, but fundamentally destructive to the DNA of the cells.

Scientists started wondering about the trade-offs made by the brain’s neural activity.

“We wondered whether there were specific mechanisms that neurons employ to mitigate this damage in order to allow us to think and learn and remember throughout decades of life,” Pollina adds.

The group focused on NPAS4, a transcription factor whose purpose was identified by Michael Greenberg’s group in 2008. In order to modulate inhibition in excitatory neurons as they react to external stimuli, NPAS4, a protein with a high degree of specificity for neurons, controls the production of activity-dependent genes.

Greenberg, the Nathan Marsh Pusey Professor of Neurobiology at the Blavatnik Institute at HMS and senior author on the new article, says: “The thing that’s been a mystery to us is why neurons have this extra transcription factor that doesn’t exist in other cell types.”

They were interested in the roles of this factor because, according to Pollina, NPAS4 is predominantly switched on in neurons in response to heightened neuronal activity that’s driven by changes in sensory experience.

In the new study, the scientists used mice to do a number of biochemical and genomic tests. First, they discovered that NPAS4 is a component of the NPAS4-NuA4 complex, which consists of 21 distinct proteins. They determined the locations of those spots after determining that the complex attaches to areas of the neuronal DNA that have sustained significant damage. More DNA breaks occurred and fewer repair factors were called upon when parts of the complex were inactivated. Also, mutations happened more slowly at sites where the complex was present than at sites where it wasn’t. Finally, mice’s lifespans were dramatically reduced when the NPAS4-NuA4 complex was missing from their neurons.

“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 adds.

It offers 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,” adds Gilliam. 

It’s this additional layer of DNA maintenance that’s buried inside the neural response to activity.

After identifying the NPAS4-NuA4 complex and outlining the fundamentals of what it accomplishes, the researchers envision a wide range of potential paths for their future study.

By examining how the process differs across animals with longer and shorter lifespans, Pollina is interested in adopting a more comprehensive perspective. Additionally, she is interested in learning more about the functioning of additional DNA repair systems in neurons and other cells, as well as how and when they are employed.

According to Pollina, this finding “opens up the idea that all cell types in the body probably specialize their repair mechanisms depending on their life span, the kinds of stimuli they see, and their transcriptional activity.

“There are likely many mechanisms of activity-dependent genome protection that we have yet to discover.”

To further understand what each protein in the complex is doing, what additional molecules are involved, and how precisely the repair process is carried out, Greenberg is keen to dive deeper into the mechanism’s specifics.

The replication of the findings in human neurons, which is currently being done in his lab, is the next step, he said.

“I think there’s tantalizing evidence that this is relevant to humans, but we haven’t yet looked in human brains for sites and damage.” he adds. “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.”

If the results are confirmed in people, they could help us understand how and why neurons break down as we age and why we get diseases like Alzheimer’s. It could also help scientists come up with ways to protect other parts of the neuronal genome that are easily damaged or treat diseases in which DNA repair in neurons goes wrong.

Source: 10.1038/s41586-023-05711-7

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