The overall goal of this project is to gain insight into the toxic mechanism of the prion protein (PrP) in transmissible spongiform encephalopathies. These rare and incurable neurodegenerative disorders occur sporadically in one out of a million individuals, but can also be passed genetically within a family, as well as through contact with infected tissues. It is widely agreed upon that PrPSc, a conformationally altered, protease resistant form of PrP, is involved in these diseases, but whether it functions as both the neurotoxic and infective molecule is unclear. Recently, a protease sensitive form of PrP containing a deletion in its hydrophobic central region (referred to as ACR-PrP) has been observed to cause an embryonic lethal phenotype in mice that can be reversed by the presence of wild-type PrP. Although artifical, ACR-PrP provides an excellent model to study the neurotoxic signaling that may be present in PrPSc infections. A cell culture assay has been developed to measure ACR-PrP toxicity and WT-PrP rescuing activity, which will be utilized in this study to perform a structure-function analysis of PrP and to provide substrate for identifying potential interactors. Assuming the mechanism of ACR-PrP is related to that of PrPSc, this information could be used in the targeting and design of future therapies for humans with prion diseases, helping to alleviate significant pain and suffering.

Public Health Relevance

Transmissible spongiform encephalopathies are rapidly progressive and invariably fatal neurodegenerative diseases caused by a confonnationally altered form of the prion protein (PrP). This study will attempt to dissect the mechanism of PrP toxicity by analyzing its structural components and identifying interacting proteins, which may provide targets for future therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
Application #
Study Section
NST-2 Subcommittee (NST)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Anatomy/Cell Biology
Schools of Medicine
Saint Louis
United States
Zip Code
Biasini, Emiliano; Unterberger, Ursula; Solomon, Isaac H et al. (2013) A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity. J Neurosci 33:2408-18
Solomon, Isaac H; Biasini, Emiliano; Harris, David A (2012) Ion channels induced by the prion protein: mediators of neurotoxicity. Prion 6:40-5
Solomon, Isaac H; Khatri, Natasha; Biasini, Emiliano et al. (2011) An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity. J Biol Chem 286:14724-36
Solomon, Isaac H; Huettner, James E; Harris, David A (2010) Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells. J Biol Chem 285:26719-26