A new study will be presented in the April 2, 2021 issue of Science. This study provides new insights into the genetic structures involved in aging, which neuro-degeneration, and may lead to the discovery of promising new treatments for diseases such as Alzheimer’s, Parkinson’s, and other age-related dementia disorders.
Neurons: Aging And Disease
“We’re optimistic about the prospects for these findings to help us better understand a variety of age-related diseases and, hopefully, to explore DNA repair as a therapeutic alternative.”
Neurons, unlike most cells, do not replace themselves over time, making them some of the longest-living cells in the human body. Due to their lifespan, it is of much more importance than they restore lesions in their DNA as they mature in order to survive over the decades of a human life cycle.
Neurons’ ability to perform these genetic repairs decreases with age as they mature; this helps us understand the reason behind why individuals experience age-related neurodegenerative disorders such as Alzheimer’s and Parkinson’s.
Lately, researchers have devised a new method called Repair-seq to explore how neurons preserve genome fitness. Through an experiment, researchers created neurons from stem cells and fed them synthetic nucleosides, which are molecules that act as DNA building blocks. These artificial nucleosides were discovered and imaged using DNA sequencing, revealing that neurons used them to repair parts of DNA weakened by natural cellular processes. Although the scientists predicted prioritization in one form or another, they were taken aback by how concentrated the neurons were on defending certain parts of the genome.
“What we saw were extremely sharp, well-defined regions of repair; very concentrated areas that were significantly higher than background levels,” says Dylan Reid, a former Salk postdoctoral scholar who is now a fellow at Vertex Pharmaceutics.
These ‘hot spots’ consisted of proteins that were related to neurodegenerative disease. Moreover, these sites have also been linked to aging.
The researchers have now discovered approximately 65,000 hot spots that covered approximately 2% of the neuronal genome. They then considered using proteomics methods to determine the proteins that were present at these hot spots, which revealed a plethora of splicing-related proteins. (These are involved in the further processing of other proteins in the long run.)
When the cells were treated with DNA-damaging agents, many of these sites tended to be very stable, and the most stable DNA repair hot spots were shown to be closely correlated with sites where chemical tags bind (“methylation”). Methylation further is better at predicting neuronal age.
Previous studies have focused on finding the regions of DNA that have damaged genetics. This study is the first time researchers have searched at areas of the genome that are heavily restored.
“We altered the model used in this study to look for restoration instead of gene destruction and that’s how we found these hot spots,” Reid explains. Evolution in modern biology helped us understand how we view nerves in the nervous system, and the more we understand that the more we will be equipped with the knowledge to improve and discover treatments to treat age-related diseases.”
Gage, who occupies the Vi and John Adler Chair for Age-Related Neurodegenerative Disease Research, further explained, “Understanding which parts of the genome might be susceptible to harm is a fascinating subject for our lab. It is only right to say that Repair-seq might turn out to be a powerful research tool.
This will help us understand the methods to study genome integrity. This might further help in figuring out diseases related to aging.