THE PRIONOSES AND OTHER CONFORMATIONAL DISORDERS

The basic pathogenesis of numerous neurodegenerative disorders is now thought to be related to abnormal protein conformation. The common the me in all these diseases is the conversion of a normal cellular and/or circulating protein into an insoluble, aggregated, beta-sheet rich fo rm which is deposited in the brain, sometimes in the form of amyloid. These deposits are toxic and produce neuronal dysfunction and death. T he most common of these illnesses is Alzheimer's disease (AD), in whic h a central event is the conversion of the normal soluble amyloid beta (sA beta) peptide to amyloid beta (A beta) within neuritic plaques an d cerebral vessels. A unique category of the conformational conditions are prion related diseases (or prionoses), where the etiology is thou ght to be related to conversion of the normal prion protein, PrPC, int o an infectious and pathogenic form, PrPSc. In the case of AD and the prionoses, the conformational change can be influenced by the presence of mutations in various gene products, as well as by chaperone protei ns. Apolipoprotein E is thought to act as such a chaperone protein in AD; however, among the prionoses such a protein has been hypothesized to exist only by indirect evidence and is called ''proteinX''. Our gro wing understanding of the mechanisms involved in this category of dise ases, raises the possibility of therapeutic approaches based directly on the prevention and reversal of pathologic protein conformation.