PP - Protein misfolding disease

Protein misfolding can occur through a number of mechanisms and lead to a large variety of disease and misfunction. One pathway for protein misfolding and pathogenesis is improper degradation of proteins. Improper degradation occurs when proteins that are partially functional and can actually benefit cellular processes are degraded despite it being detrimental to the cell. This is seen in the case of cystic fibrosis, where a deletion of a phenylalanine in CFTR leads to partial functionality but is still targeted for degradation by CHIP, a molecular chaperone which ubiquitylates the protein. CFTR is an important membrane channel for the production of mucus, which is why this improper degradation is seen in a large number of cystic fibrosis patients.  Another way in which improper folding can lead to disease is through improper localization. Improper localization occurs when misfolded proteins cannot get to where they need to go, leading to not only a loss-of-function but potential toxicity if aggregated in the wrong place. One example of this is misfolded antitrypsin, which becomes retained in the ER of liver cells and accumulates, preventing synthesis of other proteins resulting in liver damage. Also, since antitrypsin does not get secreted to its proper location, it is unable to inhibit protease activity in the lungs leading to damage in the alveoli and emphysema. Another mechanism for pathogenesis as a result of protein misfolding is dominant-negative mutations. Dominant-negative mutations are characterized by mutant proteins that compromise the function of wild-type proteins, most often in a dimer or quaternary structure. An example of this process is seen in the connective tissue disorder epidermolysis bullosa simplex. When mutant forms of keratin proteins are present, they disrupt the function of the entire keratin composed filament, leading to fragile skin that blisters easily in response to minor friction. Gain of toxic function and amyloid accumulation are two other mechanisms for pathogenesis as a result of misfolding and play a big role in neurodegenerative disorders.