The role of ribosomes in age-related diseases

Date:
January 19, 2022
Source:
Stanford University
Summary:
Research finds that the cellular assembly line that produces
proteins can stall with age, triggering a snowball effect that
increases the output of misfolded proteins. In humans, clumps
of misfolded proteins contribute to age-linked Alzheimer's and
Parkinson's diseases.



FULL STORY ========================================================================== Aging leads to a decline in cellular fitness and loss of optimal protein function. Many age-related ailments, including Alzheimer's and Parkinson's diseases, are caused by protein aggregation, a result of errors in protein folding. Yet, the mechanisms underlying how ageing causes proteins to
aggregate has largely remained a black box. In new research published
Jan. 19 in Nature, researchers at Stanford University have traced this
problem to age-dependent impairment of the machinery that produces
new proteins.


==========================================================================
To root out this issue, researchers in the lab of Judith Frydman,
the Donald Kennedy Chair in the School of Humanities and Sciences at
Stanford, focused on how age affects the functioning of ribosomes --
the cellular machinery responsible for converting messenger RNA into
proteins. They used two well- established models of human aging, yeast and roundworms. Through a combination of experiments and computational data analysis, they found that ribosome function degrades with age in both organisms. The increased load of defective proteins with age overwhelms
the protective quality control failsafes that would otherwise prevent
protein aggregation.

"We've known that protein aggregation with age is a problem linked
to many diseases. At the moment, treatments try to address it by trial-and-error testing," said Kevin Stein, lead author of the paper and
a former postdoctoral scholar in the Frydman Lab. "Getting down to the basic-biology of these diseases, and understanding what mechanisms cause
them, can help us make better decisions about what therapies could be
effective before we test them." A vulnerable time When folded correctly, proteins carry out their functions and remain soluble in the environment
of the cell. Misfolded proteins, by contrast, cannot function properly
and tend to stick to each other and other proteins, clogging up cellular processes and generating toxic aggregates. Protein aggregation has been specifically implicated in a wide variety of aging-linked diseases,
including Alzheimer's, Parkinson's, frontotemporal dementia, Huntington's disease and ALS (amyotrophic lateral sclerosis).

To guard against the continual production of misfolded proteins, cells
have dedicated "quality control" machinery for fixing or degrading
misfolded proteins. Previous research has shown that shortcomings in
these processes can lead to aggregation. This research is the first
to show the folding defect during ageing starts early in the journey
of a protein, when it is made by the ribosome. Because ribosomes are
constantly producing large amounts of proteins, these defects cause a subsequent snowball of disfunction.



==========================================================================
"One of the most vulnerable and key times in the life of a protein --
where it's most prone to misfolding -- is when it's made," said Frydman,
who is a professor of biology and of genetics.

To start, the researchers used a technique called ribosome profiling,
which allowed them to see exactly how ribosomes are moving on the
messenger RNA during the act of translation. Amassing data from all the
genes translated in young and aged Caenorhabditis elegans roundworms
and yeast, the researchers noticed that in older cells ribosomes
periodically moved more slowly and were more likely to stall and
bump into each other. As one might expect, the researchers saw that
decreases in proper ribosome performance aligned with increases in the aging-dependent aggregation of misfolded proteins. One important insight
was that the increase in stalling and misfolding overwhelmed the cell's cleaning-up-and-clearing-out quality control failsafes.

"There is a two-pronged situation where aging leads to increased stalling
and increased ribosome collisions, but the cell loses the safety net to
deal with it," explained Stein.

In follow-up experiments in worms, the researchers found that even if the overall fraction of newly made proteins with altered translation during
aging is low (~10%), this small effect can still be enough to overwhelm
the quality control system and trigger significant aggregation that can
disrupt many different cellular components or processes.

"Every cell normally makes millions of these newly translated proteins,"
said Frydman. "So very slight changes in the efficiency of folding
with age will escalate in a vicious cycle where defects in translation
lead to an overload of the system, which in turn leads to increased
protein aggregates with age that are themselves also toxic." To make
matters worse, through further experiments in yeast and C. elegans,
the researchers showed that these problems affect the very proteins that
cells use to aid in translation and to help correct misfolding issues.



========================================================================== Millions of questions While this research revealed, for the first time,
some intriguing insights about the mechanisms of aging, it inspires many questions for the future.

Perhaps the most pressing one: Why does aging affect ribosomes? Also, what
can be done about it? Given the similarities between ageing in yeast,
C. elegans and other organisms, the researchers are optimistic that their findings will translate also to humans. One direction for future work
will be the application of insights from this study to the development
of possible treatments for age-related diseases associated with protein aggregation. Excitingly, the study showed that analysis of mutations
that extend lifespan "rejuvenated" ribosomal function in aged yeast.

"This is only the beginning of a very fascinating future," said Fabia'n Morales-Polanco, a co-author of the research and a postdoctoral scholar
in the Frydman lab. "We set a precedent for something new, and there are millions of questions -- and probably hundreds of papers -- that will
follow." This research was funded by the Glenn Foundation for Medical Research, the National Institutes of Health and the Pew Charitable Trusts.

Additional Stanford co-authors of the paper are visiting graduate
student Joris van der Lienden and former postdoctoral scholar T. Kelly Rainbolt. Frydman is also a member of Stanford Bio-X, the Stanford Cancer Institute and the Wu Tsai Neurosciences Institute and a faculty fellow
of Stanford ChEM-H.

========================================================================== Story Source: Materials provided by Stanford_University. Original written
by Taylor Kubota.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kevin C. Stein, Fabia'n Morales-Polanco, Joris van der Lienden,
T. Kelly
Rainbolt, Judith Frydman. Ageing exacerbates ribosome pausing
to disrupt cotranslational proteostasis. Nature, 2022; DOI:
10.1038/s41586-021- 04295-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220119135027.htm

--- up 6 weeks, 4 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)