Date of Award

Summer 8-15-2009

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



The function of the cellular prion protein (PrPC) has remained enigmatic. In my thesis work I characterized determinant sequences necessary for the neurotoxicity and neuroprotection of the prion protein. First, I established the essential role of the N-terminal polybasic region in the toxicity of a PrP deletion mutant. Second, I characterized the normally generated C1 cleavage product as an inhibitor of prion disease pathogenesis.

Previously generated transgenic mice expressing PrP deleted for amino acids 32-134 exhibit a progressive, invariably fatal neurodegenerative illness characterized by ataxia, tremor, and a dramatic degeneration of the cerebellar granule layer of neurons. The transgenic protein expressed in these animals contains the N-terminal polybasic region composed of residues 23-31 artificially fused to the C-terminus of PrP. We investigated the role of amino acids 23-31 in delta 32-134 toxicity by generating transgenic mice expressing a PrP molecule in which residues 23-134 were deleted, resulting in a complete deletion of the N-terminus. delta 23-134 mice show no clinical or pathological neurodegenerative illness. This indicates that the N-terminal region immediately following the signal sequence cleavage site of PrP is necessary for the neurodegenerative phenotypes of Δ32-134 mice. This region has previously been shown to be essential for the constitutive endocytosis of PrPC and possesses a GAG binding consensus sequence; therefore, we investigated these putative roles of the 23-31 region in the toxicity of delta 32-134. Our data demonstrate that endocytosis of toxic PrP mutants is not required for their toxicity. We also show that endogenous GAGs are not necessary for delta 32-134 induced cell death; however, addition of high levels of exogenous GAGs can dramatically increase cellular survival. These results indicate that a nine amino acid region is essential for the toxic signaling of a mutant PrP.

The second portion of my thesis involved the characterization of the normally generated PrP cleavage product `C1' in prion pathogenesis. We generated transgenic mice expressing a PrP mutant lacking residues 23-111, which is analogous to the normally cleaved C1 fragment. We reveal that C1 lacks the ability to propagate scrapie infection on a Prn-p 0/0 genetic background; however, co-expression of C1 with full length PrPC elicits a dramatic dominant negative effect on proteinase-K resistant PrPSc formation and significantly delays neurodegenerative clinical illness. These results indicate that a natural inhibitor of prion diseases occurs normally in the brain and its regulation may serve as a therapeutic in prion diseases. In conclusion, our transgenic mouse models have identified two regions that participate in the antagonistic cell death and cell survival functions of PrPC. Most importantly, both of these regions represent therapeutic targets for the treatment of the prion diseases.


English (en)

Chair and Committee

Aaron DiAntonio

Committee Members

Thomas J Baranski, Phyllis I Hanson


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