Dementing and degenerative neurological deseases are responsible for many decastating human illnesses. As medical science has become progressively more successful, more people are living to an older age. With this change in demography has come an epidemic of a previously insignificant disorder-senile dementia. Most cases of senile dementia are due to Alzheimer's disease (AD). Not only is the cause of AD unknown, but there is no specific diagnostic test, and there is no effective treatment. The possible causes of AD include: a slow virus-like agent, a genetic disorder, accumulation of a toxin, or production of an abnormal metabolite. The many similarities between Creutzfeldt-Jakob disease (CJD) and AD have raised the possibility that a slow infectious agent might be the cause of AD; however, all attempts to transmit AD to laboratory animals have been disappointing. Recent progress has shown that a protein is required for the infectivity of the agent causing CJD and a similar neuodegenerative disease of sheep and goats, scrapie. Because the dominant molecular characteristics of these slow agents are those of a protein, and they are different from both viruses and viroids, we have chosen to label them """"""""prions"""""""" Understanding the molecular structure of slow infectious pathogens such as prions, which cause both scrapie and CJD, may help us to understand the etiology of not only AD, but also other devastating degenerative diseases of unknown etiology which afflict primarily older people. Improved purification protocols led to the identification of a 27-30 kDs protein that is a component of the scrapie prion. The unique molecular properties of the scrapie agent, or prion, appear to have defined a new class of small infectious pathogens. In this proposal, we outline studies designed to elucidate 1) the complete chemical structures of the cellular and scrapie prion proteins, 2) the molecular mechanisms of scrapie pathogenesis, 3) the cellular metabolism of the scrapie and cellular prion proteins, and 4) structure of scrapie and CJD may become the most well understood neurodegenerative diseases.
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