![]() However, the aggregation of misfolded proteins creates toxicity (toxic gain of function). If the protein is degraded and aggregation is prevented, serious pathological consequences may be avoided. Mutations that destabilize a protein can cause the loss of protein function. If it is overburdened by misfolded proteins, the unfolded protein response (UPR) triggers cell death by apoptosis 3. The endoplasmic reticulum (ER), in particular, is a major site for protein production and quality control in membrane and secretory systems. Found in all cellular compartments, chaperones act on a broad range of non-native substrates. After protein denaturation caused by stress (for example, due to heat or toxin exposure) or disease conditions, proteins can be unfolded, disaggregated and then refolded, or they can be targeted for disposal by proteolytic systems. A set of protein families termed molecular chaperones assists various processes involving folding, unfolding and homeostasis of cellular proteins. They are crucial for mitigating the deleterious effects of protein misfolding and aggregation, which, by unclear mechanisms, can cause cell death in neurodegeneration and other incurable protein misfolding diseases ( BOX 1). These quality control systems have an essential role in the life of cells, ensuring that proteins are correctly folded and functional at the right place and time 1, 2. ![]() It is mediated by chaperone and protease systems, together with cellular clearance mechanisms such as autophagy and lysosomal degradation. Protein quality control, also known as proteostasis, constitutes the regulation of protein synthesis, folding, unfolding and turnover.
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