Aging and protein homeostasis

Published on June 30, 2016   47 min
0:00
My name is Ana Maria Cuervo, and I am a professor at the Albert Einstein College of Medicine and Co-Director of the Aging Center. I will be talking today about Protein Homeostasis and its importance in aging.
0:17
As all of you know, all proteins in the cells are continuously exposed to damaging agents that can modify their protein confirmation. So when a protein is damaged, it exposes regions that are going to be particularly hydrophobic or sticky, and can abnormally interact with other proteins in the cell. To avoid that, cells count on systems that take care of protein misfolding. The first ones are chaperones that if possible will refold these proteins to return to their normal conformation. And the second system are the proteases, where chaperones deliver the unfolded protein to undergo degradation. This is actually a very conservative system because when proteins breakdown into amino acids, they can be reutilized to sustain protein synthesis. So this quality control mechanisms, chaperones and proteases are in place and functioning in all the cells when we are young. However, as we get old and in particular diseases, these systems do not work properly and result in protein toxicity or accumulation of protein damage. For example, if chaperones cannot identify, they unfold the protein or if the proteolytic systems are not ready to receive this unfolded proteins, they will accumulate inside the cell and they will organize in higher molecular weight as structures in the form of protein aggregates or oligomers that are toxic for the cell. So in this lecture, I will give you some examples of what is known about chaperone and proteolytic systems malfunctioning during aging and how can they contribute to some of the characteristics of the phenotype of ageing.
2:11
So when a protein is normally folded, it's functional, doesn't interfere with a normal homeostasis in the cell. However, if a protein is misfolded or a very different mechanism there are two major events associated to this misfolding. In one hand, there is a loss of function, whatever was the function of this protein is no longer present. So if this protein was a kinase, it will lose the ability to phosphorylate substrates in the cell. If it was transporting protein, it will lose the ability to transport proteins or other components along the cell. But in addition to this loss of function because once proteins unfold, if they are not rapidly taken care of they are going to tend to oligomerize and form this abnormal structures, that results, again, toxicity, a result from the accumulation of this altered proteins. So, when we look at the consequences of the loss of protein homeostasis, there are two fold, there is going to be a loss of function, and a gain of toxicity inside the cells. And I would to like highlight that even in some conditions, the alterations in protein homeostasis are intrinsic to the proteins because the proteins get damaged or because they do not fold properly. In other cases, these alterations in protein homeostasis result from dysfunction of the quality control mechanism inside the cell that normally take care of protein misfolding.
3:42
So through this lecture, I would like to introduce three terms, the first one is, protein homeostasis, and the other two are chaperones, and proteolytic Systems as they are the main components of the quality control systems inside the cell.
3:58
So starting with protein homoeostasis, this term refers to the series of events and cellular processes that governs the life of proteins inside cell. When you think about a protein, they are synthesized either in the cytosol or in the endoplasmic reticulum as a strain of amino acids and they require to be folded to reach their normal functional conformation. In addition, proteins are normally delivered to a specific sub-cellular compartments where they are going to be functional. This require crossing membrane, and for that the protein is going to have to partially unfold. And then refold again once it reaches the lumen of the organelle. It is very unlikely that the protein functions in isolation inside the cell. This is much more common that proteins organize into functional protein complexes. To do that, the proteins also have to undergo conformational changes that allow them to be part of this complex, through this process of assembly, or came out of this complex whenever the function have to be terminated, so through a process of the assembly. As I also mentioned, proteins can be amenable to damage and undergo partial or complete unfolding, and this is going to require chaperones for the process of refolding and repair. And also, as I mentioned, sometimes this refolding is not possible at any of these multiple steps depicted in the picture and then proteins have to be delivered for degradation. So the multiple events that we are depicting in this image require for proteins to change conformation. And in each of these steps, it is possible that unwanted regions such as hydrophobic patches get exposed. So it's essential to maintain a system or a series of systems that preserve normal protein folding or protein stability during all these steps. And this is what it constitute what is known as the protein homeostasis network.
Hide

Aging and protein homeostasis

Embed in course/own notes