For more than 30 years the major investigative focus of this laboratory has been directed toward the etiology, immunology, pathology, molecular biology, biochemistry, protein chemistry, molecular genetics of subacute progressive degenerative diseases of the nervous system. We were the first to show infection as the etiology of kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Schenker (GSS) syndrome of humans by successful transmissions to a variety of species of nonhuman primates and laboratory rodents. We have identified these human diseases and similar disease of animals (scrapie, mink encephalopathy, chronic wasting disease of deer and elk, and bovine spongiform encephalopathy (BSE) (Mad Cow disease), to be brain amyloidoses caused by posttranslational modifications of a specific host precursor protein to amyloid fibril deposits. The human and animal spongiform encephalopathies are replicating polypeptides formed de novo from the normal host precursor protein on chromosome 20 in humans and 2 in mice. We continue in our attempts to elucidate molecularly the mechanism underlying the spontaneous conformational change from normal to the infectious abnormal isoform of the protein (prion). Molecular genetic analysis of CSF/GSS/FFI already indicates several point mutations which significantly increases the probability of the spontaneous de novo conversion to an infectious polypeptide. Time-course studies relating prion protein (PrP) deposition, cytokine immunoreactivitiy, vacuolation glial activation have shown that cytokine production by activated glia occurs early resulting in neuronal apoptosis. We have successfully transmitted scrapie to cattle and convserly we have transmitted bovine spongiform encephalopathy to squirrel monkeys and two strains of mice following long asymptomatic incubation periods. We are studying strain- typing of BSE and CJD, the species barrier, the role of the spleen, PrP gene expression as it relates to disease susceptibility. We have organized seven international workshops on TSEs with emphasis on BSE and serve as the senior consultant to the Director General of WHO on TSEs (BSE) and member of the Argentine Scientific Advisory Committee on BSE.
