CHRONIC CNS DISEASE STUDIES--SLOW, LATENT AND TEMPERATE VIRUS INFECTION

研究重点是慢性退行性中枢神经系统的病因和发病机制

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 ; ALS-PD of Western Pacific; supranuclear palsy; other presenile dementias; spinocerebellar ataxias; epilepsy; chronic encephalitis with focal epilepsy; Viliuisk encephalopathy; muscular dystrophies; chronic schizophrenia; bipolar psychoses, autism; SSPE; PML; dialysis encephalopathy, goitrous cretinism; cysticercosis; and intracranial neoplasms. We have defined the transmissible and nontransmissible dementias as brain 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 conformational 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 (x10 ) 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 transmissible brain amyloidoses. Our studies focus on the elucidation of the molecular configurational events conferring the property of infectivity on a previously normal host precursor using CD spectrophotometry, high-voltage EM, MRI to elucidate the change in conformation which occurs as transmissibility is produced. 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 (protease nexin II). Posttranslational 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.