The role of ribosomes in age-related diseases

Aging impairs the ability of ribosomes to efficiently manufacture proteins and leads to protein misfolding and assembly, which disrupts cellular health and is a hallmark of many age-related diseases. (Photo credit: Felipe Serrano)

Aging leads to deterioration of cellular fitness and loss of optimal protein function. Many age-related diseases, including Alzheimer’s disease and Parkinson’s disease, are caused by protein buildup, as a result of errors in protein folding. However, the mechanisms underlying how aging causes the accumulation of proteins has largely remained a black box. In a new research published on January 19 in temper natureIn this study, researchers at Stanford University traced this problem to the age-dependent impairment of the machinery that produces new proteins.

To root out this problem, researchers in the lab of Judith Friedman, Donald Kennedy Chair in the Stanford College of Humanities and Sciences, focused on how age affects the functioning of ribosomes — the cellular machinery responsible for converting mRNA into proteins. They used two well-established models of human aging, yeast and roundworms. Through a combination of experiments and analysis of computational data, they found that ribosome function deteriorates with age in both organisms. The increased load of defective proteins with age overwhelms the protective QC protection that would prevent protein aggregation.

We have learned that protein buildup with age is a problem associated with many diseases. “Currently, treatments are trying to address them by trial-and-error testing,” said Kevin Stein, lead author of the paper and a former postdoctoral researcher in Friedman’s lab. “Referring to the basic biology of these diseases, and understanding the mechanisms that cause them, can help us make better decisions about which treatments might be effective before they are tested.”

weak time

When folded properly, proteins perform their functions and remain soluble in the cell environment. By contrast, unfolded proteins cannot function properly and tend to stick to each other and other proteins, clogging cellular processes and forming toxic aggregates. Protein accumulation is specifically implicated in a variety of diseases associated with aging, including Alzheimer’s disease, Parkinson’s, frontotemporal dementia, Huntington’s disease, and amyotrophic lateral sclerosis (AMS).

To prevent the continuous production of denatured proteins, cells assigned a ‘quality control’ mechanism to repair or degrade denatured proteins. Previous research has shown that deficiencies in these processes can lead to aggregation. This research is the first to show that a folding defect during aging begins early in the protein journey, when it is made by the ribosome. Since ribosomes constantly produce large amounts of proteins, these defects cause subsequent snowball dysfunction.

“One of the most vulnerable and most important times in a protein’s life — when it is most susceptible to misconfiguration — is when it is synthesized,” said Friedman, professor of biology and genetics.

Initially, the researchers used a technique called ribosome profiling, which allowed them to see how ribosomes move on messenger RNA during the translation process. Synthesis of data from all genes translated in the young and the elderly Certain types are elegant Roundworms and yeast, the researchers noted, that the ribosomes in the old cells were moving slower periodically and were more likely to stop and collide with each other. As one might expect, the researchers saw the decrease in proper ribosome functioning consistent with increases in the aging-dependent assembly of denatured proteins. One important insight was that the increase in stalling and poor performance overshadowed cell cleaning and removal from quality control.

“There is a two-fold situation where aging leads to increased pauses and increased ribosome collisions, but the cell loses a safety net to deal with,” Stein explained.

In follow-up experiments on worms, the researchers found that even if the total fraction of newly synthesized proteins with altered translation during aging was low (~10%), this small effect could be enough to overpower the quality control system and produce a large effect. Aggregation that can disrupt many different cellular components or processes.

“Each cell typically makes millions of these newly translated proteins,” Friedman said. “So very small changes in folding efficiency with age would escalate into a vicious cycle where defects in translation would overload the system, which in turn would lead to increased protein accumulations with age that are also toxic.”

To make matters worse, by further experimenting with yeast and C. elegansThe researchers showed that these problems affect the proteins cells use to aid translation and to help correct misconfiguration issues.

Millions of questions

While this research has revealed, for the first time, some interesting insights into the mechanisms of aging, it inspires many questions for the future. Perhaps most pressing: Why does aging affect ribosomes? Also, what can be done about it?

Given the similarities between aging in yeast, C. elegans and other organisms, the researchers are optimistic that their findings will also translate to humans. One direction of future work will be to apply insights from this study to develop possible treatments for age-related diseases associated with protein aggregation. Excitingly, the study showed that analysis of mutations that prolong ‘regenerative’ ribosome function in lifespan in aged yeast.

“This is just the beginning of a very exciting future,” said Fabian Morales Polanco, a research co-author and a postdoctoral scientist in Friedman’s lab. “We’ve set a precedent for something new, and there are millions of questions – possibly hundreds of papers – that will follow.”

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