Transmissible spongiform encephalopathies (TSE), or prion diseases, require the expression of normal host prion protein (PrP) for both replication of the infectious agent and for the manifestation of the disease pathogenesis. We have studied the effect of PrP expression in different brain cell types including neuron and astrocytes by using transgenic mice which express PrP in neurons only, astrocytes only, or in multiple cell types. All three types of mice are susceptible to scrapie infection and all succumb to the disease. Surprisingly the pathology when PrP was expressed only on astrocytes was similar to that seen when PrP was expressing in neurons as well as in multiple other cell types. Further examination revealed that abnormal PrP was localized around astrocytes, but these astrocytes were not damaged. In contrast the damage was localized to adjacent neurons. By electron microscopy the abnormal PrP was found on the astrocytes and also around neurotic process in the near vicinity of such astrocytes. Thus the neuropathogenic pathogenic process appeared to be mediated in neurons indirectly by abnormal PrP from astrocytes. In separate experiment the process of conversion of from normal to abnormal PrP was studied in vitro in a cell-free system using N-terminal PrP deletion mutants in order to examine the role of the N-terminus in this biochemical process. Deletion of residues from 32-98 caused a marked reduced in PrP conversion as well as altering the structure of the converted protein to make it more susceptible to protease K digestion at residues from 130 to 155. A similar change was observed when non-deleted mouse PrP was converted using PrP from scrapie-infected hamsters. These results suggested that altered structure of abnormal PrP might be a factor in the adaptation of the conversion process between species following cross-species infection.
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