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Researchers have spent many years in a frustrating hunt for the function of the normal PrP protein. Surely this protein must have some other reason for being than to form lethal prions. Studies showed that mice in which the PrP protein was “knocked out” were resistant to infection with the misfolded PrPSc prions. Otherwise, lacking the PrP protein seemed to have little effect.
A piece of the puzzle seems to have fallen into place. Aguzzi and other scientists reported in January 2010 in Nature Neuroscience that the protein helps maintain the myelin sheaths that surround and protect neurons in the peripheral nervous system. In mice engineered to lack PrP, peripheral nerves suffered progressive damage as a result of demyelination. Aguzzi said in an interview in the journal that he suspects PrP plays a similar role in higher mammals.
The finding may also bear on another longstanding enigma: are prion diseases caused by a “gain-of-function” process—the misfolded protein itself damages nerve cells—or a “loss-of-function” change, in which conversion of the normal protein to prions robs the nerves of something they need to stay healthy?
Outside the nervous system, another hint of PrP's normal function came in a 2006 report from the Lindquist lab. The scientists found that expression of the protein in stem cells is necessary for the self-renewal of blood-manufacturing tissues in bone marrow. The study showed that all long-term hematopoietic stem cells express PrP on their surfaces and that blood-forming tissues lacking PrP in stem cells exhibited increased sensitivity to cell depletion.
HHMI scientists have begun to decipher another prion riddle—the existence of distinct “strains” of prions that produce different phenotypes. For example, the PrPSc prion causes several distinct neurological diseases in animals and humans. Each disease is slightly different in the length of its incubation period, the typical symptoms, and the areas of the brain that are damaged.
“This was one of the most intriguing and challenging questions,” explains Weissman. In viruses or bacteria, strain differences are specified by instructions in their genetic code. If prions lacked any genetic material at all, where were the blueprints that determine strains?
Weissman carried out a series of experiments demonstrating that prions could propagate as distinct strains, each specified by different arrangements of atoms in the protein's structure. The structural configuration of a prion strain was the blueprint for making more copies—no DNA required.
Using the powerful yeast system, Weissman and colleagues created synthetic prions with different configurations that generated phenotypically diverse strains. In another experiment, they analyzed two distinct strains of the yeast protein Sup35, one of which was strongly infectious and the other weakly infectious.