Studies focus on causes and pathogenesis of chronic degenerative CNS disorders with emphasis on MS; Parkinson's, Pick's, Huntington's and Alzheimer's diseases; ALS/PD of Western Pacific; supranuclear palsy; other presenile dementias; spinocerebellar ataxias; epilepsy; chronic encephalitis with focal epilepsy; Viliuisk encephalopathy; muscular dystrophies; chronic schizophrenia; autism; SSPE; PML; dialysis encephalopathy; goiterous cretinism; cysticercosis; and intracranial neoplasm. We have defined the transmissible and nontransmissible dementias as cerebral amyloidoses caused by post-translational modification of a specific host precursor protein to amyloid fibril deposits. We now recognize the slow unconventional viruses causing kuru-CJD-scrapie as replicating polypeptides formed de novo from a normal host precursor protein, specified on chromosome 20 in man and 2 in mice. The molecular elucidation of the spontaneous configurational change to infectivity, basically a crystallographic problem, is now becoming our major target. Molecular genetic analysis of familial CJD already indicates several point mutations which enormously increase (X106) the probability of this spontaneous de novo conversion to an infectious polypeptide. Microbiology must now contend with a totally new paradigm for replicating, infectious, pathogenic agents in the nontransmissible brain amylodoses. Our studies focus on the elucidation of the molecular configurational events conferring the property of infectivity on a previously normal host precursor. In normal aging, Alzheimer's disease (AD), and Down's syndrome a different host precursor protein (specified on chromosome 21 in man, 16 in mice) is a cell excreted inhibitor of growth factors. Post-translational degradation of this normal precursor forms the 42 amino acid amyloid polypeptide which polymerizes to form the deposits of amyloid angiopathy, amyloid plaques and neurofibrillary tangles in aging, AD and Down's. This occurs in all individuals who reach their 90s. Genetic, toxic, and infectious factors may accelerate this aging brain amyloid deposition. Conventional viruses causing slow, infectious, degenerative disease are intensely studied to elucidate the neurotropism and mechanism of pathogenesis: retrovirus encephalomylopathies of HTLV-L and HIV (of AIDS),- herpesviruses (HSV, CMV, EB and virus varicella-zoster); papovaviruses (JC),- RSSE; measles; SSPE; and many chronic virus infections of amyloid.
