How brain cells repair their DNA reveals ‘hot spots’ of aging and disease

Neurons lack the capacity to replicate their DNA, so they are constantly working to repair damage to their genome. Now, a new study from Salk scientists finds that these repairs are not random, but rather focus on protecting certain genetic “hot spots” that appear to play a critical role in neuronal identity and function.

The results, published in the April 2, 2021 issue of Science, provide new insights into the genetic structures involved in aging and neurodegeneration, and may indicate the development of potential new therapies for diseases such as Alzheimer’s disease, Parkinson’s disease and other dementia-related disorders. age.

“This research shows for the first time that there are sections of the genome that neurons prioritize for repair,” says Salk professor and chair Rusty Gage, co-author of the article. “We are excited about the potential of these findings to change the way we view many age-related nervous system diseases and potentially explore DNA repair as a therapeutic approach.”

Unlike other cells, neurons generally do not replace each other over time, making them one of the most living cells in the human body. Their longevity makes it even more important for them to repair damage to their DNA as they age, in order to maintain their function over decades of human life. As we age, the ability of neurons to make these genetic repairs decreases, which could explain why people develop age-related neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease.

To study how neurons maintain genome health, the study authors developed a new technique they call Repair-seq. The team produced neurons from stem cells and fed them with synthetic nucleosides – molecules that serve as the building blocks of DNA. These artificial nucleosides could be found by DNA sequencing and imaged, showing where neurons used them to repair DNA damaged by normal cellular processes. While scientists expected to see some prioritization, they were surprised by the focus of neurons on protecting certain sections of the genome.

“What we saw were incredibly sharp, well-defined repair regions; highly focused areas that were significantly higher than background levels,” says Dylan Reid, co-lead author and co-correspondent, former postdoctoral fellow. de Salk and now a researcher at Vertex Pharmaceuticals. “The proteins that are found at these ‘hot spots’ are implicated in neurodegenerative diseases, and the sites are also linked to aging.”

The authors found around 65,000 hot spots that covered around 2% of the neural genome. They then used proteomic approaches to detect proteins found at these hot spots, involving many proteins related to splicing. (These are involved in the eventual production of other proteins.) Many of these sites appeared to be quite stable when cells were treated with DNA damaging agents, and the most stable DNA repair hot spots were found to be strongly associated with the sites where chemical tags attach (“methylation”) which are the best predictors of neuronal age.

Previous research has focused on identifying which sections of DNA suffer from genetic damage, but this is the first time that researchers have looked for where the genome is heavily repaired.

“We turned the paradigm from looking for damage to looking for repair, and that’s why we were able to find these hot spots,” says Reid. “This is really new biology that could potentially change the way we understand neurons in the nervous system, and the more we understand this, the more we can seek to develop therapies to treat age-related diseases.

Gage, who holds the Vi and John Adler Research Chair in Age-Related Neurodegenerative Diseases, adds: “Understanding which areas of the genome are vulnerable to damage is a very exciting topic for our lab. We believe Repair-seq will be a powerful tool. research tool, and we continue to explore additional new methods to study genome integrity, particularly in relation to aging and disease. “

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