What was the discovery of Harvard scientists that could predict future treatments for Alzheimer’s disease?

Those who play sports know that muscle that is not worked is lost. It happens with our whole body, including our mind, especially as we get older. However, it seems that when it comes to brain not everything works the same way. While the use of brain cells may help maintain memory and other cognitive functions throughout life, scientists have found that the associated activity also damages neurons by inviting more breaks in their DNA, so how do they stay in shape? This is the question that a team from Harvard Medical School (HMS) tried to answer in a recent article that has just been published in the journal Nature.

Specialists have identified a new DNA repair mechanism that it occurs exclusively in neurons, which helps explain why they continue to function despite their intense repetitive work. Specifically, the results show that a protein complex called NPAS4-NuA4 initiates an activity-induced DNA break repair pathway in neurons.

“Further research is needed, but we think this is a really promising mechanism to explain how neurons maintain their longevity over time,” said co-lead author Elizabeth Pollina, who carried out the work. as a fellow at HMS and is now a researcher. developmental biology assistant at Washington University School of Medicine.

If the results are confirmed by further studies in animals and then in humans, they could help scientists understand the exact process by which brain neurons break down during aging or in neurodegenerative diseasesa decisive involvement in finding possible options for its treatment or prevention.

In the vast landscape of cell types in the body, neurons stand out: unlike most other cells, they do not regenerate or replicate. They work tirelessly to reshape themselves in response to environmental cues, ensuring the brain can adapt and function throughout life. This remodeling process is accomplished in part by activating new gene transcription programs in the brain. Neurons use these programs to convert DNA into protein assembly instructions.

However, this active transcription in neurons has a high cost: makes DNA vulnerable to breakage, damaging the genetic instructions needed to make proteins so essential to cellular function. “There is this contradiction at the biological level: neuronal activity is essential for the performance and survival of neurons, but it is inherently damaging to the DNA of cells,” said co-lead author Daniel Gilliam, student graduated from the neuroscience program at hum.

Researchers have been interested in how the brain balances the costs and benefits of neural activity. “We wondered if there were specific mechanisms that neurons use to mitigate this damage to allow us to think, learn, and remember across decades of life,” Pollina said.

The team focused their attention on NPAS4, a transcription factor whose function was discovered by Michael Greenberg’s lab in 2008. A protein known to be highly neuron-specific that regulates activity-dependent gene expression for controlling the inhibition of excitatory neurons when they respond to external stimuli.

“What’s been a mystery to us is why neurons have this extra transcription factor that doesn’t exist in other cell types,” said Greenberg, Nathan Marsh Pusey professor of neurobiology at the Institute. HMS Blavatnik and lead author of the new paper. .-. NPAS4 is primarily 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.”

In the new study, the researchers performed a series of biochemical and genomic experiments in mice. First, determined that NPAS4 exists as part of a complex made up of 21 different proteins, known as NPAS4-NuA4. They then established that the complex binds to heavily damaged sites on neuronal DNA and mapped the locations of these sites.

When the components of the complex were inactivated, more DNA breaks occurred and fewer repair factors were recruited. Additionally, sites where the complex was present accumulated mutations more slowly than sites without the complex. Finally, mice lacking the NPAS4-NuA4 complex in their neurons had a significantly shorter lifespan.

“What we discovered is that this factor plays a critical role in initiating a new DNA repair pathway that can prevent the disruptions that occur with transcription in activated neurons,” said Pollina said. “It is this extra layer of DNA maintenance that is built into the neural response to activity,” Gilliam added, “and provides a potential solution to the problem that a certain amount of activity is required to maintain neural health and longevity, but the activity itself is also detrimental.

The researchers see many future directions for their work now that they have identified the NPAS4-NuA4 complex and laid the groundwork for what it does. Pollina wants to take a broader view, exploring how the mechanism varies between the longest and shortest-lived species. He also wants to study whether there are other DNA repair mechanisms, in neurons and other cells, how they work and in what contexts they are used. “I think it’s conceivable that all cell types in the body probably specialize their repair mechanisms based on their lifespan, the types of stimuli they receive, and their transcriptional activity,” Pollina said. There are probably many activity-dependent genome protection mechanisms that we have not yet discovered.”

For his part, Greenberg is eager to delve into the details of the mechanism to understand what each protein in the complex does, what other molecules are involved, and how exactly the repair process takes place. “The next step,” he said, “is to replicate the results in human neurons.”, work already in progress in his laboratory. “I think there’s some tantalizing evidence that it’s relevant to humans, but we haven’t looked at people’s brains for sites and damage yet,” he said. It may turn out that this mechanism is even more prevalent in the human brain, where there is much more time for these breaks to occur and for DNA repair.”

If confirmed in humans, the findings could provide insight into how and why neurons break down with age and when neurodegenerative diseases such as Alzheimer’s disease develop. It could also help scientists devise strategies to protect other regions of the neuronal genome that are susceptible to damage, or to treat disorders in which DNA repair in neurons fails.

Other study authors were Cindy Lin, Naomi Pajarillo, Christopher Davis, David Harmin, Ee-Lynn Yap, Ian Vogel, M. Aurel Nagy, Emi Ling, Eric Griffith, Charles Weitz, Erin Duffy, Andrew Landau, and Bernard Sabatini .

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