Harvard Medical School Researchers Discover Novel DNA Repair Mechanism That May Help Scientists Understand How Brain Neurons Breakdown As We Age And In Neurodegenerative Diseases
Keeping the mind active by engaging in activities such as reading, playing games, and learning a new skill is thought to boost cognitive health as adults age.
Although using brain cells may help retain memory and other cognitive functions, scientists have also suggested that the activity damages neurons by inviting more DNA breaks.
This points to the age-old question, “How can neurons remain functional and healthy throughout individuals’ lifetimes?”
And recently, a research team from Harvard Medical School set out to answer this question. Through a study conducted on mice, they identified a novel DNA repair mechanism that exclusively occurs in neurons– which starts to explain why neurons continue functioning in the long term in spite of tough repetitive work.
The researchers specifically found that NPAS4–NuA4, a protein complex, opens a pathway in order to repair DNA breaks caused by neuronal activity.
“More research is needed, but we think this is a really promising mechanism to explain how neurons maintain their longevity over time,” said Elizabeth Pollina, the study’s co-first author.
If further animal and human studies are conducted, and the findings are confirmed, then scientists may better understand the breakdown process of brain neurons during aging and with neurodegenerative diseases.
Neurons are unlike most cells in the human body in that they do not replicate or regenerate. So, year after year, neurons work hard to change and remodel themselves in response to cues in our environment. This ensures that our brains can appropriately adapt and operate in the long term.
The process of remodeling is partly due to the activation of new gene transcription programs in the brain. Neurons utilize these programs to transform DNA into instructions for the assembly of proteins.
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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.
Now that the NPAS4-NuA4 complex has been identified, the team believes this discovery can aid a vast amount of research possibilities.
Pollina, for instance, hopes to study how this mechanism varies among shorter and longer-lived species.
Greenberg, on the other hand, wants to dive deeper into the mechanism’s details– studying what each protein in the complex is responsible for, how the process of repair is carried out, and what other molecules are involved.
For this research, he claimed that the next step is to replicate the mice study’s results in human neurons.
“I think there is tantalizing evidence that this is relevant to humans, but we haven’t yet looked in human brains for sites and damage. 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,” Greenberg said.
If Greenberg’s theory is correct, then this may provide priceless insight regarding why neurons break down as adults age and develop neurodegenerative diseases like Alzheimer’s disease.
Likewise, the findings may help scientists develop tactics to protect neuronal genome regions that are more prone to damage.
To read the study’s complete findings, which have since been published in Nature, visit the link here.
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