We have continued to focus our research studies on the etiology, immunology, pathology, molecular biology, biochemistry, protein chemistry, and molecular genetics of subacute progressive degenerative diseases of the nervous system. Particular emphasis is placed on a group of rare diseases which we have identified as the transmissible spongiform encephalopathies (TSEs). This group consists of four human diseases--kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker diseases (GSS), and fatal familial insomnia (FFI); and five diseases of animals--scrapie, transmissible mink encephalopathy (TME), chronic wasting disease of deer and elk (CWD), feline spongiform encephalopathy (FSE) and bovine spongiform encephalopathy (BSE). We have demonstrated that these diseases are cerebral amyloidoses caused by posttranslational modification of a specific host precursor sialoglycoprotein resulting in the formation of amyloid fibrils. The normal cellular protein is on chromosome 20 in humans and 2 in mice and the abnormal isoform is formed de novo. The human diseases occur sporadically (80%), iatrogenically (2%) or as autosomal dominent genetic/infectious diseases. By molecular genetic techniques we have identified more than 15 point mutations which significantly increases the probability of the conversion of the cellular protein to an infectious polypeptide. During the period of this report we have continued our attempts to elucidate the mechanism underlying the spontaneous conformational change from normal cellular protein to its infectious abnormal isoform (prion). We now have successfully transmitted BSE to squirrel monkeys, capuchin monkeys and two strains of mice. Passage through nonhuman primates has led to transmissions to hamsters thereby broadening the range of species susceptibility. Studies employing the new varient CJD (nvCJD) are underway in laboratory rodents and nonhuman primates. We are attempting to purify and sequence the normal cellular protein of humans and fish. We have isolated PrPres from tonsillar biopsy tissue from a patient who has a positive 14-3-3 protein in CSF. To our knowledge this is the first such isolation in the United States. Inasmuch as the patient had multiple surgical procedures performed on her in the United Kingdom and since isolation of PrPres from human tonsillar has only been demonstrated in nvCJD in the UK neuropathological study of brain obtained at autopsy will be important.
