Different versions of RNA encoded by single genes may play a role in Alzeimer's disease, new research suggests. These genetic molecules could point to new treatments and ways to spot the disease before its symptoms set in, scientists hope.
The new study, published Wednesday (May 22) in the journal Nature Biotechnology, zooms in on RNA, a cousin of DNA. Among other functions, RNA copies instructions from DNA and relays them to a cell's protein builders. Through a process called "alternative splicing," though, one gene can give rise to many versions of RNA, called isoforms, which in turn may play very different — or even opposite — roles in cell function.
This is possible because genes are made up of building blocks called exons and introns. The exons contain the important instructions for making proteins, and to make RNA, cellular machinery typically "splices" out the introns, leaving only exons behind. But alternative splicing opens the door to new possibilities — the cell might cut out some exons along with the introns, or perhaps leave a few introns in the final RNA molecule. The mastermind behind this snipping process is known as the spliceosome, and its splicing is directed by various molecules in the cell.
Thus, thanks to the spliceosome, one gene can make many RNA, although "most genes only express a single isoform," said senior study author Mark Ebbert, a principal investigator and assistant professor at the University of Kentucky College of Medicine. "There's a large proportion that have multiple, but there are some that have a wild number," occasionally in the tens or hundreds.
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In their new study of human brain tissue, Ebbert and his colleagues uncovered 700 RNA isoforms that had never been described before. And they found that the levels of nearly 100 of these isoforms differed in the brains of people with and without Alzheimer's.
Notably, the genes behind these isoforms were equally active in both groups of people. This suggests that if scientists only look at a gene's overall activity but not at the different RNAs it's making, they miss out on this nuance.
"Part of what we're trying to highlight is, look at all this we don't understand," Ebbert told Live Science.
For the study, the team analyzed brain tissue from 12 deceased organ donors who were between 75 and 90 years old when they died; six of the donors had Alzheimer's disease while six had no cognitive impairment. The researchers used a technique called "long-read sequencing" to take a snapshot of RNA present in the brain tissue.
Isoforms born from the same gene tend to be "very similar to each other," said co-first author Bernardo Heberle, a doctoral candidate in Ebbert's lab. So if you analyze only a short snippet of each RNA, "you really can't tell if the fragment came from isoform A, B or C," Heberle told Live Science. Long-read sequencing, as its name suggests, looks at long strings of RNA, enabling researchers to capture differences in the isoforms that might be missed in shorter reads.
Of the 700 newfound isoforms, 430 could be connected back to known genes, and of those, 53 came from genes that had been tied to health conditions in previous studies. Notably, two genes related to the abnormal amyloid and tau proteins seen in Alzheimer's — APP and MAPT — respectively gave rise to five and four isoforms.
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A few isoforms stood out when the team compared the brains of the Alzheimer's patients to those without the disease. For example, a gene called TNFSF12 made two distinct isoforms, the first of which was boosted in the brains of people with Alzheimer's and the second of which was higher in healthy brains. In the past, the TNFSF12 gene has been tied to the brain inflammation seen in Alzheimer's disease — but because the gene makes multiple isoforms, more work may be needed to reveal which one is actually behind this inflammation.
However, because the recent study included only 12 brains, it's too soon to know if these results carry over to others with and without Alzheimer's, the researchers stressed.
To expand their data set and see which results do carry over, co-first author Ja Brandon, a research assistant professor at the University of Kentucky College of Medicine, is now leading an effort to conduct the same study with more than 300 brains. In the long run, the researchers hope certain RNA isoforms may be prime targets for future Alzheimer's drugs.
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