Proteins are functionally important molecules in cells. They are made of amino acids, "strung together" with peptide bonds, and folded into a 3-D structure according to the chemical bonding properties of the amino acids. They are flexible molecules, which can change conformation (shape) depending on the environment they are in or the function they are performing; however, they normally keep one general shape. Proteins have different levels of structure. The primary structure is the amino acid sequence. The secondary structures are different shapes that regions of proteins may take-for example, alpha helices or beta sheets. Alpha helices are right-handed spirals and beta sheets are made up of multiple parallel strands that look like pleated sheets. The tertiary structure of a protein involves the rest of the folding of the protein into a complete three-dimensional structure, and the quaternary structure is the way in which proteins may interact, for example proteins coming together to form a larger unit.
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The protein of interest in prion disease is called a prion, which is an acronym for "proteinaceous infectious particle" or "PrP." The non-infectious version of this protein is referred to as PrPC , the C referring to cellular, whereas the infectious version is called PrPSc, the Sc standing for "scrapies," which was the first form of prion disease found and originated in sheep. Most PrPs are encoded by the same nucleotide sequence of DNA, the gene PRNP,and are made normally in the body. This was confusing when it was first discovered because people thought that if prion proteins were normally present in the body, then they could not possibly be pathogenic. Nevertheless, there is a difference and what separates infectious prion proteins from the non-infectious versions normally present in the body is the conformation of the protein. Infectious proteins have a different conformation than normal prion proteins even though they are made of the same amino acid sequence, and this change in shape dramatically affects their properties in the cell.
Normal cellular prions have an unknown function, but they are highly expressed in brain tissues, especially in neurons in the cerebellum, cerebral cortex, hippocampus, medulla and thalamus (Rosenberg, 2007). There are many different hypotheses as to what PrPC does normally in the brain, including copper use, homeostatic regulation, cellular signalling, influencing synaptic function, and protecting neurons agains cell death, as well as perhaps a function in the immune system. It is known that normal prions are a membrane protein in neuronal cells, so their function may have something to do with the way a neuron cell interacts with the surrounding cells and environment. Although prion proteins must have some function in normal organisms, "knock-out" mice lacking the PRNP gene (the DNA sequence that codes for the prion protein) seemed to be normal, so it does not appear to be an essential protein for survival (Cobb, 2009).
PrPSc has a very stable conformation that makes it difficult to destroy. The normal methods of protein destruction, UV or ionizing radiation, heat, strong chemicals, and proteases (enzymes that break down proteins), are ineffective in denaturing and destroying these infectious particles. This resistance to breakdown is an important property that helps explain their role in neurodegeneration, which will be discussed later. Researchers do not know the exact structure of normal and infectious prions, but there is some information as to the differences. It is thought that PrPC are a predominantly alpha-helical protein, whereas the conformation changes to include more beta-sheets in PrPSc (Prusiner, 2004).
The exact mechanism by which PrPSc spreads is not fully known, but the general system of PrPSc reproduction is hypothesized. It is thought that a "misfolded" PrPSc will interact with the normal prion proteins in the cell and when it comes into contact with them, it will change their conformation to the infectious form. How exactly it induces this conformational change is not known, but something about the interaction between the normal and infectious protein changes the normal protein to become infectious. As this occurs, more and more of the normal prions are changed over to infectious prions, resulting in a domino effect in which all of the newly infectious particles will change over the normal particles. Once the transformation has begun, it speeds up dramatically over time, but this slow start accounts for the prolonged incubation period of prion diseases before symptoms arise.