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8.15: Diseases of folding and misfolding

  • Page ID
    4819
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    If a functional protein is in its native (or natural) state, a dysfunctional misfolded protein is said to be denatured. It does not take much of a perturbation to unfold or denature many proteins. In fact, under normal conditions, proteins often become partially denatured spontaneously, normally these are either refolded (often with the help of chaperone proteins) or degraded (through the action of proteosomes and proteases). A number of diseases, however, arise from protein misfolding.

    Kuru was among the first of these protein misfolding diseases to be identified. Beginning in the 1950s, D. Carleton Gadjusek (1923–2008)249 studied a neurological disorder common among the Fore people of New Guinea. The symptoms of kuru, which means "trembling with fear”, are similar to those of scrapie, a disease of sheep, and variant Creutzfeld-Jakob disease (vCJD) in humans. Among the Fore people, kuru was linked to the ritual eating of the dead. Since this practice has ended, the disease has disappeared. The cause of kuru, scrapie, and vCJD appears to be the presence of an abnormal form of a normal protein, known as a prion (mentioned above). We can think of prions as a type of anti-chaperone. The idea of proteins as infectious agents was championed by Stan Prusiner (b. 1942), who was awarded the Nobel Prize in Medicine in 1997250.

    The protein responsible for kuru and scrapie is known as PrPc. It normally exists in a largely α-helical form. There is a second, abnormal form of the protein, PrPsc for scrapie; whose structure contains high levels of β-sheet. The two polypeptides have the same primary sequence. PrPsc acts to catalyze the transformation of PrPc into PrPsc. Once initiated, this reaction leads to a chain reaction and the accumulation of PrPsc. As it accumulates PrPsc assembles into rod-shaped aggregates that appear to damage cells. When this process occurs within the cells of the central nervous system it leads to neuronal cell death and dysfunction, and severe neurological defects. There is no natural defense, since the protein responsible is a normal protein.

    Disease transmission: When the Fore ate the brains of their beloved ancestors, they inadvertently introduced PrPsc protein into their bodies. Genetic studies indicate that early humans evolved resistance to prion diseases, suggesting that cannibalism might have been an important selective factor during human evolution. Since cannibalism is not very common today, how does anyone get such diseases in the modern world? There are rare cases of iatrogenic transmission, that is, where the disease is caused by faulty medical practice, for example through the use of contaminated surgical instruments or when diseased tissue is used for transplantation.

    But where did people get the disease originally? Since the disease is caused by the formation of PrPsc, any event that leads to PrPsc formation could cause the disease. Normally, the formation of PrPsc from PrPc is very rare. We all have PrPc but very few of us spontaneously develop kuru-like symptoms. There are, however, mutations in the gene that encodes PrPc that greatly enhance the frequency of the PrPc→PrPsc conversion. Such mutations may be inherited (genetic) or may occur during the life of an organism (sporadic). Fatal familial insomnia (FFI)251 is due to the inheritance of a mutation in the PRNP gene, which encodes PrPc. This mutation replaces the normal aspartic acid at position 178 of the PrPc protein with an asparagine. When combined with a second mutation in the PRNP gene at position 129, the FFI mutation leads to Creutzfeld-Jacob disease (CJD)252. If one were to eat the brain of a person with FFI or CJD one might well develop a prion disease.

    So why do PrPsc aggregates accumulate? To cut a peptide bond, a protease (an enzyme that cuts peptide bonds) must position the target peptide bond within its catalytic active site. If the target protein's peptide bonds do not fit into the active site, they cannot be cut. Because of their structure, PrPsc aggregates are highly resistant to proteolysis. They gradually accumulate over many years, a fact that may explain the late onset of PrP-based diseases.

    Contributors and Attributions

    • Michael W. Klymkowsky (University of Colorado Boulder) and Melanie M. Cooper (Michigan State University) with significant contributions by Emina Begovic & some editorial assistance of Rebecca Klymkowsky.


    This page titled 8.15: Diseases of folding and misfolding is shared under a not declared license and was authored, remixed, and/or curated by Michael W. Klymkowsky and Melanie M. Cooper.

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