BAG2 Condensates Show That There is Much Left to Explore in the Realm of Cellular Maintenance

There are likely many processes and components involved in cellular maintenance that remain poorly explored, with the work here on BAG2 condensates serving as an example of the type. Cells work to remove damage, and many lines of evidence show that enhancing that outcome improves cell and tissue function, slowing aging. Much of this work emerges from the study of calorie restriction as a means to extend life in short-lived species, but that is just one slice of a much broader area of research. It remains an open question as to whether any of this will lead to effective ways to slow aging in humans, however, given that ways to enhance, say, the processes of autophagy have so far proven disappointing in humans, failing to improve significantly upon the effects of exercise or a lowered calorie intake.

Biomolecular condensates are organelles that don't have the recognizable cell membrane enclosure, but instead, are separated from the surrounding cytoplasm by a difference in density that can be loosely compared to a drop of oil in water. This liquid-liquid phase separation creates a specialized, relatively concentrated environment for certain functions and reactions. For example, a stress granule is a membraneless organelle that appears when the cell is under stress - maybe there's too much glucose, maybe it's too hot or cold, maybe the cell is experiencing dehydration - and its job is to sweep up RNA floating around in the cytoplasm, storing those genetic instructions and pausing their translation into proteins.

"When there's stress, what happens to the proteins that are already in the cell? If they're under those stress conditions, some of those proteins could get damaged and they could misfold." Misfolds of the tau protein, for example, can become pathological and turn into the neurofibrillary tangles that characterize Alzheimer's disease. This is where the newly discovered BAG2 condensate comes in. Named for the BAG2 protein that it contains, the organelle is capable of sweeping up these faulty proteins in the cytoplasm and stuffing them into a proteasome - the cell's version of a trash can - located in the organelle. This inactivates and breaks down the protein. Many proteasomes are present in cells at any given time, he added, but what makes this particular proteasome (labeled 20S) special is that it can accept proteins that are already somewhat misfolded and would not fit in the other cellular trash cans.

Additionally, this method of protein degradation does not rely on the ubiquitination process, in which proteins meant for destruction are marked with a tiny ubiquitin protein tag before being grabbed by the proteasome. The role of the BAG2 protein in this context is not yet fully defined, but researchers suspects that it may have a role in helping organize the messy protein before it goes into the 20S proteasome. "What these BAG2 condensates seem to do, at least in the case of tau, is they can actually travel to the damaged tau and gobble it up. The BAG2 condensate really is an ideal place for damaged tau. It would be really nice to figure out how we can shuttle tau into this condensate at the early stages of its damage for the cell to get rid of it, before it gets worse."


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