At various stages of youth and maturity, the team analyzed the killifish's genes. In the aging killifish, they discovered that the brain and other tissues were not the only ones with aggregates. There was a tendency for more than half of the aggregated proteins to aggregate.
The difference between one tissue and another was 888-609- 888-609- 888-609- 888-609- While many of the proteins were expressed at similar levels in multiple tissues, they did not clump together in other tissues.
David said the amount of tissue specificity of the proteome was amazing. She and other researchers believe that the differences are related to how cells maintain their quality. Cells use elaborate machinery to make sure that the long, chainlike peptides are folded properly and that they are chopped up for reuse. Jarosz said that tissues may vary in how much they rely on certain parts of the process.
A huge mystery in human biology is why neurodegenerative diseases are so 888-609- 888-609- 888-609- 888-609- 888-609- The causes of Alzheimer's disease and Parkinson's disease are not well understood. She said that the possibility that different cells have different quality is an explanation for why different tissues behave differently.
Studies of worms and flies show that animals age more quickly if the machinery that keeps the stability of the proteins is perturbed. Animals tend to live longer if their genes are altered. It doesn't mean that aging is caused by aggregation, but it does mean that the two are closely related.
In order to further investigate the relationship between aggregation and aging, the researchers looked at the proteins in the killifish that age quickly. The length of dividing chromosomes is preserved by the telomerase gene in these fish.
Jarosz said that he and his colleagues expected to find less aggregates in the gut and other tissues that grew quickly. Fast-growing tissues aged more rapidly than tissues that grew slowly.
Problems with the cell's control over the quality of its proteins could be the reason. Damage from aggregates may build up with each cell division if cells lose control over their processes. Tissues that grow quickly have more chance to accumulate harm.
Sometimes aggregate is difficult to explain. It turns out that part of the answer is connected to a mechanism that cells use to control their genes.
The activities and functions of the proteins they made up were dictated by the complex 3-D shapes that were folded into them. In the last decade or so, it was found that a growing list of proteins have an insturment that doesn't fold into a stable shape. The process of forming droplets, or condensates, is similar to the process of "phase separation" that separates oil from water. It can increase the activity of the enzymes by concentrating them together or by sequestering them. Cells can use condensates to fine tune their activity by changing the concentration of their own genes.
The disordered regions of proteins can cause them to stick together more permanently and wreak havoc. A chain reaction of aggregation can be caused by the misfolds and aggregate themselves of some defects. This is similar to what happens in "mad cow disease" and variant Creutzfeldt-Jakob syndrome, in which abnormal folding of prions in the brain causes a wave of abnormal brain tissue.
Control mechanisms come with risks. The cost of being vulnerable to many aging-associated diseases seems to be worth it in evolutionary terms.
An illustration of this emerged in a second preprint posted in March, in which the team homed in on a molecule called DDX5 that is found in killifish brains. DDX5 serves a variety of important functions in the body and helps to make sure that other proteins are made correctly. The researchers predicted that DDX5 was likely to behave like a prion and that one misfolded DDX5Protein promotes the misfolding and aggregation of other DDX5 molecule.
A variety of other proteins were found in the clumps of DDX5 as well. Aggregates can act as sticky blobs that can interfere with cellular functions.
He said that it suggests that we have the ability to aggregate with age and that it can be done in a prionlike way.
The same region that makes DDX5 prone to aggregation was found to be the same region that made it possible for condensation. There is a link between control over the natural function and aggregate. Labbadia said it's a catch-22.
Jarosz said that the disordered domain isn't needed for activity as narrowly defined. It is important that that activity is used in the living system.
There is a huge, fantastic, big controversy in the field about what causes aggregates to form. Eliminating important cellular functions is one of the benefits of aggregates. Aggregates may affect cell survival.
An example of the protective effect is found in studies of the huntingtin protein. Huntingtin is important for the healthy development of the nervous system in people with Huntington's disease. There are toxic segments that damage the nervous system.
Steve Finkbeiner, a researcher on aging at the University of California, San Francisco, was studying aggregation of huntingtin at the time. The team showed that the neurons that had aggregates of huntingtin lived longer than the ones that didn't.
It was the first proof that aggregate formation was a response to other forms of the misfolded proteins.
Since then, he and others have shown that this protective aggregation response can occur in other neurodegenerative diseases as well. He said that if the amyloid plaques characteristic of the disease form to protectively bind up the defect, then breaking up the plaques might do more harm than good.
It is difficult for humans to understand that abnormal things should be bad. It is important that people don't jump to conclusions because biology is complex.
The picture emerging clearly now is that the phenomenon is not limited to neurodegenerative diseases and can be found in every cell of the body. It is a universal challenge for every cell to deal with the tendency of DDX5 to aggregate.
Since cells have been dealing with this problem for a long time, it's possible that preventing aggregation has been a major force in the evolution of the sequence. Natural selection is likely to be very strong because of the tendency of abundantProteins to aggregation. The conclusion is supported by the observation that in young animals, the more abundant the proteins, the less likely they are to cause problems. A faster evolutionary rate is associated with a propensity to aggregate.
The killifish's brain was the most affected by this effect. The researchers think that the key to innovations in the organ may have been the scuplture. The brain's evolution may have made it more vulnerable to diseases caused by aggregation.
Jarosz said that it is likely that every organ has to find a different balance between doing its job and managing. Intestinal cells turn over constantly, endocrine cells make and excrete hormones, immune cells spring to action when they detect invaders, the brain processes information, and so on and so forth. The evolved strategies for dealing with aggregation will vary from tissue to tissue and from animal to animal. The brain has evolved so much in the past few years that it may not have had enough time to evolve adequate protections against the aggregation of new genes.
Every day there is a fundamental problem of aggregation for all organisms. The prionlike DDX5 has an inherent propensity to aggregate, and the organisms tries to protect itself against it. We all have to deal with it.
She said that the aging of organisms as disparate as yeast, worms, flies, fish, mice and humans, means that we should pay more attention to this.
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