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

Neurons lack the power to copy their DNA, in order that they’re always working to repair harm to their genome. Now, a brand new examine by Salk scientists finds that these repairs usually are not random, however as an alternative concentrate on defending sure genetic “hot spots” that seem to play a crucial function in neural identification and operate.

The findings, printed within the April 2, 2021, subject of Science, give novel insights into the genetic buildings concerned in aging and neurodegeneration, and may level to the event of potential new therapies for ailments such Alzheimer’s, Parkinson’s and different age-related dementia issues.

“This research shows for the first time that there are sections of genome that neurons prioritize when it comes to repair,” says Professor and Salk President Rusty Gage, the paper’s co-corresponding creator. “We’re excited about the potential of these findings to change the way we view many age-related diseases of the nervous system and potentially explore DNA repair as a therapeutic approach.”

Unlike different cells, neurons typically do not change themselves over time, making them among the many longest-living cells within the human physique. Their longevity makes it much more vital that they repair lesions in their DNA as they age, to be able to keep their operate over the many years of a human life span. As they grow old, neurons’ potential to make these genetic repairs declines, which may clarify why individuals develop age-related neurodegenerative ailments like Alzheimer’s and Parkinson’s.

To examine how neurons keep genome well being, the examine authors developed a brand new method they time period Repair-seq. The group produced neurons from stem cells and fed them artificial nucleosides — molecules that function constructing blocks for DNA. These synthetic nucleosides might be discovered through DNA sequencing and imaged, exhibiting the place the neurons used them to make repairs to DNA that was broken by regular mobile processes. While the scientists anticipated to see some prioritization, they have been shocked by simply how centered the neurons have been on defending sure sections of the genome.

“What we saw was incredibly sharp, well-defined regions of repair; very focused areas that were substantially higher than background levels,” says co-first and co-corresponding creator Dylan Reid, a former Salk postdoctoral scholar and now a fellow at Vertex Pharmaceutics. “The proteins that sit on these ‘hot spots’ are implicated in neurodegenerative disease, and the sites are also linked to aging.”

The authors discovered roughly 65,000 sizzling spots that coated round 2 % of the neuronal genome. They then used proteomics approaches to detect what proteins have been discovered at these sizzling spots, implicating many splicing-related proteins. (These are concerned within the eventual manufacturing of different proteins.) Many of these websites seemed to be fairly steady when the cells have been handled with DNA-damaging brokers, and essentially the most steady DNA repair sizzling spots have been discovered to be strongly related to websites the place chemical tags connect (“methylation”) which are greatest at predicting neuronal age.

Previous analysis has centered on figuring out the sections of DNA that undergo genetic harm, however that is the primary time researchers have seemed for the place the genome is being closely repaired.

“We flipped the paradigm from looking for damage to looking for repair, and that’s why we were able to find these hot spots,” Reid says. “This is really new biology that might eventually change how we understand neurons in the nervous system, and the more we understand that, the more we can look to develop therapies addressing age-related diseases.”

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

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Materials offered by Salk Institute. Note: Content could also be edited for fashion and size.

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