Link Identified Between Neuronal DNA Repair and Neurodegeneration

A new study led by researchers from the Salk Institute gives novel insights into the genetic structures involved in aging and neurodegeneration, and points  to the development of potential new therapies for diseases such Alzheimer's, Parkinson's and other age-related dementia disorders. The findings were published in Science. 

"This research shows for the first time that there are sections of the genome that neurons prioritize when it comes to repair," says Rusty Gage, the paper's co-corresponding author. "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."

To investigate how neurons maintain genomic health, the study authors developed a new technique they term Repair-seq. The team produced neurons from stem cells and fed them synthetic nucleosides. These artificial nucleosides could be found via DNA sequencing and images, showing where the neurons used them to make repairs to DNA that was damaged by normal cellular processes. While the scientists expected to see some prioritization, they were surprised by just how focused the neurons were on protecting certain 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 author Dylan Reid. "The proteins that sit on these 'hot spots' are implicated in neurodegenerative disease, and the sites are also linked to aging."

The authors found approximately 65,000 hot spots that covered around 2 percent of the neuronal genome. They then used proteomics approaches to detect what proteins were found at these hot spots, implicating many splicing-related proteins. Many of these sites appeared to be quite stable when the cells were treated with DNA-damaging agents, and the most stable DNA repair hotspots were found to be strongly associated with sites where chemical tags attach that are best at predicting neuronal age.