Over time, a relatively minor mistake in protein production at the cellular level may lead to serious neurological diseases.
But exactly how the cell avoids such mistakes has remained unclear until now. Researchers at Ohio State University found the mechanism that prevents such errors, and explain their findings in the Proceedings of the National Academy of Sciences.
“Cells normally make a certain amount of mutant proteins, and use a series of degradation and recycling steps to get rid of them,” said Michael Ibba, the study's lead author and an associate professor of microbiology at Ohio State University.
“But sometimes the cell produces more mutations than it can handle. That buildup can overwhelm the cell's ability to eliminate these mutants.”
Left unchecked, these errors result in the buildup of faulty proteins within the cell. This buildup happens during translation, a process that cells use to make usable proteins. Over time, the researchers believe that the accumulated proteins might cause neurological diseases, such as Alzheimer's and Parkinson's.
Scientists know that cells use many enzymes to carry out translation properly. The enzymes that make the building blocks for translation carefully check for errors before proteins are made. If they find an error, they instruct the cell to destroy these building blocks, which are called aminoacyl-tRNAs. Cells break down these aminoacyl-tRNAs through a process called hydrolysis, in which one compound is split into other compounds in a reaction that uses water.
Ibba and his team work with a special family of enzymes called the aminoacyl-tRNA synthetases. These enzymes select the amino acids inside the cell that are used for producing proteins.
Ibba and his colleagues used a specific synthetase, phenylalanyl-tRNA synthetase, to investigate what happens when the wrong amino acid is selected. They carried out their experiments in a strain of E. coli bacteria cells.
They changed certain components of the translation process and found that the replacements halved hydrolysis, and in some cases reduce hydrolysis by as much as 90 percent. In other experiments, the researchers also slightly modified the protein. Further tests showed that this alteration left the modified enzymes incapable of preventing mistakes during protein production.
“It revealed an essential function for this group of enzymes in hydrolysis,” Ibba said.
In related work, Ibba and other researchers have found that bacteria grow poorly or die when this enzymatic step is missing.
“We knew it was an important process for the cell, but until this study, we didn't know exactly why it was so important,” Ibba said. “Other researchers have actually disrupted this process in mice, and found that it leads to neurodegenerative diseases resembling Alzheimer's and Parkinson's.”
Ibba and his team face more challenges. They want to know precisely how cells correct for these mistakes, and knowing this may give them insight to neurological diseases.
“The key to efficient cell growth is to limit the level of mistakes to a tolerable amount,” Ibba said. “In spite of all its checks and balances, a cell isn't perfect. Even though textbooks tell you that gene expression is flawless, this just isn't possible in real life.
“Ultimately – and it's a long way off – we hope to develop a way to therapeutically correct for these errors,” he said. “If we understand how these diseases start, and it relates to mistakes in the mechanism we studied, then there may be a means to try and correct these mistakes.”
Ibba conducted the study with Ohio State colleagues Jiqiang Ling, a graduate research associate in the Ohio State Biochemistry Program, and Hervé Roy, a postdoctoral researcher in microbiology.
This study was supported by a grant from the National Science Foundation.
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