Inducible Prion Diseases Caused by Artificial Mutation

Prions have generated considerable interest in the scientific community because they are an entirely new class of infectious agents. Unlike viruses, which replicate using the genetic information contained in their genome (nucleic acid), prions are devoid of nucleic acids. They are composed entirely of a single infectious protein. It has recently been discovered that the replication of prions requires an interaction between the incoming infectious prion protein and the normal cellular prion protein synthesized by the host cell. This interaction promotes the conversion of the normal protein into additional infectious ones. Studying prion diseases in experimental animal: models has provided significant insight Into human neurodegenerative disorders. One of the most promising fronts in the battle against Alzheimer’s disease, which continues to devastate a large segment of the aging population, is the study of prion diseases in experimental animal models. Although they occur relatively rarely in humans (about 1 in 1 million people are affected), prion diseases exhibit marked similarities to Alzheimer’s disease (AD). Both are late onset neurodegenerative disorders resulting in dementia and death; and both, importantly, are characterized by protein deposits, known as amyloid plaques, in the brain. These plaques result from the abnormal processing of a protein, Alzheimer’s precursor protein in AD and the prion protein (PrP) in conditions such as Creutzfeldt-Jacob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. In contrast to the normal form of the protein, which presents in a more helical form (a-helix), the plaques feature an abnormal configuration of protein chains packed side by side in flat sheets (~-sheets). A number of studies have established that prion diseases are disorders of protein conformation and it seems likely this will also be the underlying mechanism in AD. Genetically-engineered mice (transgenics) in which various forms of the prion gene have been introduced provide models for both hereditary and infectious prion diseases. The introduction of the human prion gene in transgenic mice renders them susceptible to human prions. Similar models have been obtained for other species, such as sheep and hamsters, using an identical approach. Since both prion diseases and AD are late onset, we plan to study the temporal development of prion diseases in adult animals. To do so, we intend to establish a transgenic model in which the expression of the prion protein gene can be regulated by tetracycline fed to the animals through their normal drinking water. Once established, this system will be used to activate or repress a special prion gene with an artificial mutation designed to create prions spontaneously to induce neurodegeneration in transgenic mice. This will enable us to assess the effect of activating or repressing the prion gene at various time points during the progression of the disease. The second objective is to dissect the prion protein to find domains which can inhibit the formation of infectious prion proteins. Evidence already indicates that a region of the prion protein binds to another cellular protein whose activity is critical in the formation of the infectious prion protein. By introducing this protein region in transgenic mice already predisposed to develop scrapie, we believe that we will inhibit development of the disease. Such approach may assist us in pioneering new therapeutic strategies for human neurological disorders.