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= Loss of Proteostasis  =

Lead Section : Hallmark Summary :
 * The proteome, the entirety of proteins expressed in an organism, is significant to the function of the cell because proteins encode for essential structures and functional products. Proteostasis describes a state in which the expressed proteins in an organism are in homeostasis, marked by optimal regulation of protein expression, degradation, and their roles in signaling pathways.
 * Loss of proteostasis, as a result of aging, causes defects in the machinery that regulate the proteome of an organism. This can result in a variety of harmful effects on the cell, such as the accumulation of defective proteins, proteins that are not effectively expressed, and defective chaperone proteins. Typical protein unfolding is caused by heat shock, ER stress and oxidative stress. However, the cell has specific mechanisms by which it addresses the natural aggregation of mis-folded or non-functional proteins. These mechanisms become less regulated over time, and causes the aggregation of non-functional proteins that contribute to aging in the model organism. The three main mechanisms that prevent the loss of proteostasis are the ubiquitin-proteasome system, the autophagy-lysosomal system, and chaperone mediated protein folding. The autophagy-lysosomal system, and ubiquitin-proteasome system support proteostasis by facilitating the degradation of non-functional proteins . Autophagy is a process by which an organism not only carries out the degradation of faulty proteins, but also accelerates protein turnover. Chaperone proteins facilitate protein refolding, in order to ensure protein stability and quality.

Ubiquitin-Proteasome System
Essentially, the ubiquitin proteasome system utilizes a variety of enzymes, and ubiquitin tagging in order to direct non-functional proteins to be degraded in the proteasome complex. The main enzymes present in this system are known as E1, E2, and E3. E2 is the most central enzyme in this system because it carries out ubiquitin tagging, on proteins that are non-functional. Proteins tagged with ubiquitin are guided into the proteasome complex to be degraded. This process process prevents the aggregation of non-functional proteins, which contributes to aging.

Chaperone Mediated Protein Folding
Chaperones are a group of proteins that influence covalent protein folding, and protein unfolding in order to ensure the stability of the proteome. Chaperone proteins have a variety of roles in the cell which include, preventing aggregation, ensuring that proteins follow a protein folding pathway, and facilitating the process of folding newly synthesized proteins.

Autophagy-Lysosomal System
Authophagy is the degradation of damaged or non-functional material in the cell, such as organelles or proteins. The process of autophagy is carried out by autophagosomes, and is typically triggered when the cell experiences stress. Autophagy can be carried out in three distinct methods known as chaperone mediated autophagy, macroautophagy, and microautophagy. All three of these methods result in the damaged cell material from the cytoplasm being lead to the lysosome lumen for degradation.

Progress since the Hallmarks of Aging (2013)
The hallmarks of aging outlines the mechanisms by which the cell maintains optimal protein regulation, which include chaperone-mediated protein folding, the autophagy-lysosomal system, and the ubiquitin-proteasome system. In the hallmarks of aging there is a figure that outlines three endogenous and exogenous forms of stress that initiate protein unfolding, and how subsequent pathways involving the previously stated mechanisms can be affected by the aggregation of mis-folded and non-functional proteins.

In one study performed after 2013, a transgenic mouse model was constructed to have a defects in chaperone mediated autophagy, specifically in liver tissues. With this induced defect, caused by the deletion of L2A in the liver, it was clear that there was a decline in proteostasis in the model organism, due to vastly reduced levels of chaperon mediated autophagy. Inducing the decline of chaperone-mediated autophagy in the hepatic system of mice, caused greater vulnerability to oxidative stress, the inability to metabolize drugs, as well as reduced hepatic function overall. Thus, compromising the chaperone medediated protein folding in this tissue has greater effects on the overall function of this tissue, due to non-functional proteins, that code for essential functional products in the cell.

Other studies in aging and longevity have taken a different approach, and seek to preserve or maintain proteostasis in a model organism to demonstrate how proteostasis influences longevity. Experimental methods can be used to induce moderate heat stress, a natural exogenous occurrence in the cell, in order to trigger autophagy in a model organism that normally experiences a decline in the autophagy-lysosomal system with age. Many studies talk about hormesis, a method which induces moderate quantities of stress to the organism, which can have beneficial effects, such as increased longevity. In this study exposing the model organism, C. elegans, to hormetic heat stress induces autophagy, which becomes less regulated with age. Inducing autophagy resulted in greater stress resistance and longevity in the model organism, as a result of maintaining proteostasis via the autophagy-lysosomal system.

In another study a transgenic fruit fly model was developed to over express FOXO, in order to improve the functionality of the ubiquitin-proteasome system with age. Moderate over-expression of dFOXO in heart tissue of D. melanogaster, resulted in improved protein maintenance mainly in the the ubiquitin-proteasome system, but also in the autophagy-lysosomal system. Over-expressing this gene had downstream effects on the ubiquitin-proteasome system, which allowed it to work at an optimal level, even in aged D. melanogaster. Greater protein regulation, caused by moderate over-expression of dFOXO in the heart tissue, significantly improved overall function of this tissue in aged fruit flies.

An abundance of aging research focuses on the investigation of protein aggregates, in order to quantify aggregation in specific tissues, and how it affects tissue function. A study conducted on the skeletal muscle in humans focuses on quantifying protein aggregates in tissue samples obtained from a biopsy in order both old and young subjects. The skeletal muscle samples in older subjects contained 2 fold more protein than the younger subjects. Given these quantifications, this study was applied to skeltal muscle in C. elegans to see the true effects of aggregation on skeletal muscle. It was clear that protein aggregation, a result of loss of proteostasis, caused decreased muslce mass, and decreased mobility.

Overall, these recent studies seek to understand the greater implications of dysfunction in the proteome, by examining the machinery that maintains optimal protein regulation in the cell. These mechanisms are meant to promote protein turnover, and eliminate the build up of non-functional proteins, because optimal protein function is essential to the overall health of the organism, given that proteins have diverse roles in the cell.