Mechanisms of prion strain selection

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Prion diseases are a group of emerging transmissible neurodegenerative diseases of humans and animals. Prion diseases of humans can be caused by interspecies transmission, for example, variant Creutzfeldt- Jacob disease is caused by transmission of bovine spongiform encephalopathy to humans. Following interspecies transmission, adaptation of prions to a new host species can involve competition between prion strains until one prion strain predominates. The long-term goal of this laboratory is to describe the mechanism(s) of prion adaptation to a new host species. In a step to achieve this goal, we plan to investigate the molecular basis of prion strain selection. We have developed a prion strain selection model where hamsters are first infected in the sciatic nerve (i.n.) with the drowsy (DY) strain of transmissible mink encephalopathy (TME), then i.n.superinfected with the hyper (HY) strain of TME. Using this model, we have localized the site of prion strain selection to the lumbar spinal cord, most likely within ventral motor neurons (VMNs). We hypothesize that alterations in prion agent transport and/or prion agent replication are responsible for prion strain selection within the central nervous system. To investigate this hypothesis we will i) establishing the degree to which DY TME infection alters axonal transport of a retrograde tracer or epitope or fluorescently labeled PrPSc from the sciatic nerve to VMNs in the lumbar spinal cord ii) determine the effect of DY TME replication in VMNs has on subsequent HY TME replication in VMNs by Western blot analysis and/or animal bioassay of microdisseced VMNs and iii)assess the effect of DY TME infection on the viability of VMNs which are the first cell type infected by HY TME following sciatic nerve inoculation by quantifying VMN populations using unbiased stereology. Results from the aims in this proposal will define the mechanism(s) of prion selection, begin to address the factor(s) that prions compete for, and advance our understanding of how prions adapt to a new host species following interspecies transmission.