Prion diseases are fatal neurodegenerative disorders of humans and animals. A wealth of evidence suggests that the central molecular event in these diseases is the conformational conversion of PrPC, a normal cell-surface glycoprotein, into PrPSc, an abnormal isoform that is infectious in the absence of nucleic acid. Although we now have a detailed picture of how PrPSc figures in the disease process, the normal biological function of PrPC has remained a mystery. The major objective of this grant is to investigate an exciting new hypothesis concerning the physiological function of PrPC. We propose that PrPC plays a key role in protection of cells from pro-apoptotic stresses, and that subversion of this cytoprotective activity causes neurodegeneration. First, we will utilize novel, genetically-based screens in yeast, in addition to proteomics technologies, to identify interacting proteins that play a role in the cytoprotective and cytotoxic actions of PrP. Next, we will investigate the mechanisms underlying the cytoprotective effects of PrPC using a variety of biochemical and cell-based approaches. Finally, we will utilize transgenic mice to analyze the role of Bax in the neurotoxic actions of PrPSc and other abnormal forms of PrP. In addition to elucidating the normal function of PrPC, our findings are likely to provide insights into the mechanisms by which prions cause neurodegeneration, and will yield clues as to how this process can be blocked as a therapeutic strategy. The PrP-interacting proteins and cellular pathways identified here may also be relevant to other neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases, in which cellular stress plays a prominent role.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Wong, May
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Boston University
Schools of Medicine
United States
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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
Turnbaugh, Jessie A; Unterberger, Ursula; SaĆ”, Paula et al. (2012) The N-terminal, polybasic region of PrP(C) dictates the efficiency of prion propagation by binding to PrP(Sc). J Neurosci 32:8817-30
Biasini, Emiliano; Turnbaugh, Jessie A; Massignan, Tania et al. (2012) The toxicity of a mutant prion protein is cell-autonomous, and can be suppressed by wild-type prion protein on adjacent cells. PLoS One 7:e33472
Biasini, Emiliano; Turnbaugh, Jessie A; Unterberger, Ursula et al. (2012) Prion protein at the crossroads of physiology and disease. Trends Neurosci 35:92-103
Solomon, Isaac H; Biasini, Emiliano; Harris, David A (2012) Ion channels induced by the prion protein: mediators of neurotoxicity. Prion 6:40-5
Westergard, Laura; Turnbaugh, Jessie A; Harris, David A (2011) A nine amino acid domain is essential for mutant prion protein toxicity. J Neurosci 31:14005-17
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
Westergard, Laura; Turnbaugh, Jessie A; Harris, David A (2011) A naturally occurring C-terminal fragment of the prion protein (PrP) delays disease and acts as a dominant-negative inhibitor of PrPSc formation. J Biol Chem 286:44234-42
Massignan, Tania; Biasini, Emiliano; Harris, David A (2011) A Drug-Based Cellular Assay (DBCA) for studying cytotoxic and cytoprotective activities of the prion protein: A practical guide. Methods 53:214-9
Turnbaugh, Jessie A; Westergard, Laura; Unterberger, Ursula et al. (2011) The N-terminal, polybasic region is critical for prion protein neuroprotective activity. PLoS One 6:e25675

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