Scientists have long wondered how neurons remain healthy and functional throughout life, carrying out their vital work in the brain without needing to be renewed. Now a team at Harvard Medical School has identified a new DNA repair mechanism that occurs exclusively in neurons, some of the longest-lived cells in the body. The research, conducted in mice and published in Nature, helps explain why neurons continue to function over time despite intense repetitive work.
If the findings are confirmed in more animal and human studies, they could help scientists understand the precise process by which neurons in the brain break down during aging or in neurodegenerative diseases.
Furthermore, it could provide clues about how and why neurons break down as we age and when we develop neurodegenerative diseases such as Alzheimer’s. It could also help scientists develop strategies to protect other regions of the neuronal genome that are prone to damage or to treat disorders in which DNA repair in neurons fails.
The identified mechanism is a protein complex called NPAS4-NuA4 that has been shown to initiate a pathway to repair activity-induced DNA breaks in neurons.
“More research is needed, but we think this is a really promising mechanism to explain how neurons maintain their longevity over time,” says co-author Elizabeth Pollina.
Neurons, unlike most other cells, do not regenerate or replicate. Day after day, year after year, they work tirelessly to adapt in response to environmental cues, ensuring that the brain can adapt and function throughout life.
This remodeling process is accomplished in part by activating new programs for gene transcription in the brain. Neurons use these programs to convert DNA into instructions for assembling proteins. However, this active transcription in neurons comes at a high cost: it makes DNA vulnerable to breakage, damaging the genetic instructions needed to make proteins that are so essential for cell function.
We think this is a really promising mechanism to explain how neurons maintain their longevity over time.
Elizabeth Pollina
washington university
“There is this contradiction at the biological level: neural activity is essential for the performance and survival of neurons, but it is inherently damaging to the DNA of cells,” says co-lead author Daniel Gilliam.
“We wondered if there were specific mechanisms that neurons use to mitigate this damage in order to allow us to think, learn and remember throughout decades of life,” says Pollina.
The team turned its attention to NPAS4, a protein known to be highly specific for neurons. NPAS4 regulates activity-dependent gene expression to control inhibition in excitatory neurons as they respond. to external stimuli.
“NPAS4 is mainly activated in neurons in response to elevated neuronal activity driven by changes in sensory experience, so we wanted to understand the functions of this factor,” adds Pollina.
In this study, a series of biochemical and genomic experiments were performed in mice.
“What we found is that this factor plays a pivotal role in initiating a new DNA repair pathway that can prevent disruptions that occur alongside transcription in activated neurons,” Pollina explains.
NPAS4 complex
Now that the researchers have identified the NPAS4-NuA4 complex and established the basics of what it does, they see many future directions for their work.
“I think it opens up the idea that all cell types in the body probably specialize their repair mechanisms based on their lifespan, the types of stimuli they see, and their transcriptional activity,” Pollina said. There are probably many activity-dependent genome protection mechanisms that we have yet to discover.”
The next step is to replicate the results in human neurons..
“I think there is tantalizing evidence that this is relevant to humans, but we have not yet looked at human brains for sites and damage. It may turn out that this mechanism is even more prevalent in the human brain, where you have much more time for these breaks to occur and for DNA repair to occur,” they conclude.