image: R-LOOPS, A COMMON GENOMIC TANGLE THAT OCCURS MORE FREQUENTLY AS WE AGE, MAY BE CREATING CELLULAR STRESS THAT CUMULATIVELY LEADS TO SOME OF THE CHANGES SEEN IN ALZHEIMER'S.
Credit: National Institutes of Health (NIH)
A look at neurodegenerative disease in the context of the aging brain will test the link between peculiar genomic structures in the cells, called R-loops, known to cause DNA damage as we age and diseases like Alzheimer’s disease. Purdue University researcher Hana Hall, whose work shows that preventing R-loops, which consist of DNA and RNA tangles, slows neuronal aging, will investigate their role in neurodegenerative disease with the support of a $2.45 million R01 grant from the National Institute of Health.
The brain of a person with Alzheimer’s disease is characterized by clumps of misfolded amyloid beta protein, accumulations of the protein tau, and inflammation, changes that build up over time. Scientists don’t know whether those changes are the cause or effect of the disease, but they are certainly the result of processes that have gone awry. Hall suspects that more frequent occurrence of R-loops could be creating cellular stress that cumulatively leads to some of the changes seen in Alzheimer’s disease.
“By the time we diagnose Alzheimer’s disease the damage is done, but that damage has been building for decades. said Hall, a research assistant professor of biochemistry in the College of Agriculture, and an expert in DNA damage and aging. “What if we can find out when the problem begins and go to that place to begin prevention?”
One way to prevention may lie in the series of chemical reactions, or pathways, that lead to R-loop formation. With the NIH grant, Hall will investigate a pathway involving specific chemical marks, such as N6-methyladenosine or m6A, which is known to help clear the RNA-DNA tangles. The brain cells of patients with Alzheimer’s have low levels of m6A, and Hall’s work with test the link.
“We know that R-loops accumulate in aging neurons and I propose that a similar process is occurring during neurodegenerative disease, but it’s accelerated,” Hall said. “There are many pathways in the aging brain that are mis-regulated, and I think R-loop accumulation significantly contributes to the problems.”
Ordinarily, the RNA chain hangs off the DNA as it is assembled, detaching when the copy is complete. But sometimes, the RNA binds to the section of DNA, causing a roadblock in gene expression. Cells have many mechanisms to prevent or remove R-loops. But if those fail, the cell snips the bound section of an RNA-DNA tangle and clears it out of the nucleus. That resolves the roadblock, but creates two problems: first, in one part of the cell, the RNA-DNA hybrids attract the attention of the immune system, causing inflammation; and second, the DNA left in the nucleus is now damaged.
“Loss of chemical marks, such as m6A stabilizes R-loops, which can result in more DNA damage,” Hall said. “Our cells can repair DNA, but as we age, DNA repair is not as efficient, so we have more R-loops, and more DNA damage. And that’s very dangerous for cells.”
Stable R-loops are a particular problem for neurons, which don’t replace themselves like the other cells in our body. Thus, problems like R-loops accumulation in neuronal cells over the course of our life may lead to damaged genes and loss of neuronal functions.
As part of the grant, Hall will use fruit flies, an excellent model organism to study aging and Alzheimer’s disease, to modulate levels of m6A and observe whether that reduces the amount of stable R-loops and consequently DNA damage. Although approximately 70% of human disease-associated genes are conserved in fruit flies, the next step for Hall will be to research the link between R-loops, genome instability, and neuroinflammation in mammalian model organism such as rat neuronal cell cultures seeded with human brain tau.
In her 2022 paper published in Aging Cell, Hall showed the reducing levels of R-loops in the photoreceptor neurons in the fly retina slowed the progressive loss of visual function.
“That really was the first paper looking at R-loops during neuronal aging,” Hall said. “That discovery gave us a boost in confidence to propose, that similarly to aging, diseased neurons may be damaged as a consequence of R-loop accumulation.”
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