The long term objectives of this application are to determine how to prion protein becomes modified in infected animals, and how this modification may produce cell injury. Investigation of a new incident of transmissible mink encephalopathy (TME) has resulted in the identification of two distinct disease syndromes in hamsters. The first has an incubation period of sixty-five days and has the predominant clinical signs of hyperesthesia and cerebellar ataxia. The second syndrome has an incubation period of 160 days and is clinically characterized by lethargy with no hyperesthesia or cerebellar ataxia. Each syndrome has been """"""""cloned"""""""" by serial passage at high dilution. Examination of the prion protein (PrP) in each of these syndromes has revealed differences in solubilities, protease sensitivities, and molecular weights. This is the first time that PrP differences have been seen in two distinct syndromes in a single outbred species. Therefore, the differences in PrP observed can not be due to changes in primary amino acid sequence, but rather to posttranslational modification.
The specific aims of this proposal are to biochemically characterize the PrPs from the two syndromes in an attempt to identify conformational and/or other posttranslational modifications to these proteins which may effect their processing within the cell and influence the disease syndrome produced. Furthermore, it may be possible to determine if the different PrPs induce their associated syndromes in a """"""""strain-specific"""""""" manner by testing other infected species (mink, cattle, squirrel monkeys) for specific PrP isoforms. This proposal is relevant to human dementias of the Alzheimer's type because it will attempt to determine biochemical differences in the amyloid-like prion protein from two distinct clinical syndromes in hamsters. Changes identified may explain differences observed in the solubility, protease sensitivity, and molecular weights of the proteins. These findings may further relate to changes in protein processing in the brain which influence the course and type of disease produced.
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