Everyone knows that damage done to DNA is a problem. However, no one assumed that the damage done to mRNA would ever be a problem. Well they were very wrong. A group of scientists at Washington University in St. Louis discovered one very important factor that may be key to understanding diseases like Alzheimer's.
"Everybody thought, 'Why care about the messenger RNA? These molecules have high turnover rates and are quickly degraded, so what does it matter if one is damaged?'" said Hani Zaher, PhD, assistant professor of biology in Arts & Sciences at Washington University in St. Louis.
"In organisms like E. coli or yeast, that's probably true," Zaher said. "You don't have to worry about mRNA because it turns over really fast. But in neurons you can't use that argument because an mRNA can persist, in some cases for days. And if that mRNA is really damaged it can become a big problem." He also stated that Under normal conditions only about 1 percent of the cellular mRNAs are oxidized, but if you have oxidative stress, for whatever reason, a higher percentage can be damaged.
One of the hallmarks of Alzheimer's is oxidative stress, and studies have shown that in people with advanced Alzheimer's, half of the RNA molecules in the neurons may be oxidized."
When the team at Washington fed oxidized mRNA to ribosomes it appeared that they jammed and stopped. It was said that a frozen ribosome could be rescued by factors that released it from the mRNA however, later chewed up and damaged. With these certain factors missing, damaged mRNA accumulated in the cell, just as it does in Alzheimer's.
It's known that when DNA is transcribed to mRNA, there is a mistake 1/10,000 times. This means when the mRNA is translated to protein, there might be an error 1/1000 times. To test the theory the team was given mRNA transcripts to ribosomes. They damaged one letter in a three-letter mRNA coding unit, oxidizing a G (the base guanine), to create what is called 8-oxo-G.
"We expected that we might get aberrant proteins," Simms said. "But the ribosome didn't make mistakes. It just stopped. It couldn't deal with the mRNA at all"
Because of their finding, they wanted to go further into detail. Simms built a longer 300-nucleotide mRNA to use. And instead of adding the damaged mRNA to a reconstituted bacterial system, she put it in extracts of plant and animal cells. They wanted to rear it with something called "no-go decay"What they found made them question whether or not if oxidized mRNA was the target. To further test everything they turned to yeast. The yeast ribosomes jammed on the oxidized mRNA but were rescued by no-go decay…This caused very little damaged mRNA to accumulate in the cell. Because of this discovery, Simms was able to delete a gene for a factor that releases the ribosomes from the mRNA when it jams. When she did that, the level of oxidized mRNA went up so she then deleted a gene factor that is recruited to degrade the mRNA after the ribosome is released, and again the level of oxidized mRNA rose. Without no-go decay, the cells were clearly in trouble.
Zaher said "The system that translates mRNA into protein is highly conserved, so what's true for yeast is probably true for people as well… Is oxidized mRNA implicated in disease? Science recently published work showing that mice with a double defect in their translation system have severe neurodegenerative disease”
With the information they now have, who knows how far they can go to repair these damaged mRNA in patents with Alzheimer's? After that who knows how far it could go with all neurodegenerative diseases. This is an amazing discovery and I think a lot of progress will be made within the next couple of years.
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