Dissecting Prion Disease Mechanisms with Transgenic Mice

Dartmouth College, Hanover NH

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Abstract

The objective of my research is to understand how altered conformations of the prion protein (PrP) arise and produce disease. During the project period, I expressed mutant PrP genes in scrapie-infected neuroblastoma (ScN2a) cells and transgenic (Tg) mice, and studied the pathological and biochemical changes induced by these mutations. These studies generated several significant results. (1) I established that a 106 amino acid PrP deletion mutant PrP(delta23-88,delta141- 176), designated PrP106, forms infectious miniprions efficiently in Tg mice. I also found that PrP106 molecules are destabilized and spontaneously adopt a conformation poised to form prions. (2) I discovered that a shorter PrP deletion mutant PrP(delta23-88,delta141-221), designated PrP61, spontaneously forms amyloid rods and causes apoptotic neurodegeneration when expressed in Tg mice. (3) Finally, I demonstrated that three different strains of murine prions cause scrapie in Tg(PrPl06)Prnp 0/0 mice. In this application for a two-year extension to my original award, I propose to pursue three new, important experiments based on my interim results. * I will use PrP106 as a substrate to generate minipdons efficiently in vitro. * I will inoculate synthetic PrP61 peptides into indicator animals to determine whether these peptides can cause infectious prion disease. * Finally, I will use pathological and immunological assays to determine whether passage through Tg(PrP106)Prnpa0/0 mice caused three different murine prion strains to converge into one phenotype or whether they remained distinct.