According to the "protein-only hypothesis," infectious prions are composed exclusively of a misfolded glycoprotein, PrPSc, which is formed by conformational change of a chemically indistinguishable host protein, PrPC. Prions can exist in multiple, self- replicating strains, characterized by unique clinical, pathological, and biochemical features. A phenomenon not easily explained by the protein-only hypothesis is selective neurotropism, in which the pattern of PrPSc accumulation in different brain regions is determined by the prion strain. The mechanism(s) by which cells recognize and distinguish between different prion strains remains unknown. In this competitive renewal application, we propose three specific aims to determine the molecular basis of prion neurotropism. 1. Test the hypothesis that PrPSc glycosylation controls the neurotropism of prion strains. 2. Test the hypothesis that accessory polyanions control the neurotropism of prion strains. 3. Compare the composition of prion deposits associated with different strains.

Public Health Relevance

Transmissible Spongiform Encephalopathies (TSEs), also known as prion diseases, are a unique group of slowly progressive and invariably fatal infections of the central nervous system, which can occur in infectious, sporadic, and inherited forms. Some examples of TSEs include kuru and Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in deer and elk, transmissible mink encephalopathy (TME) in mink, and scrapie in sheep. The infectious agents of TSEs are unconventional, proteinaceous entities, which have been termed prions. In this application, we propose to study the mechanisms responsible for prion dissemination through the brain. These studies may eventually lead to improved methods to diagnose and treat prion TSEs, and may also provide insights into the pathophysiology of related neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Wong, May
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Dartmouth College
Schools of Medicine
United States
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Supattapone, Surachai (2014) Elucidating the role of cofactors in mammalian prion propagation. Prion 8:100-5
Zurawel, Ashley A; Walsh, Daniel J; Fortier, Sean M et al. (2014) Prion nucleation site unmasked by transient interaction with phospholipid cofactor. Biochemistry 53:68-76
Supattapone, Surachai (2014) Synthesis of high titer infectious prions with cofactor molecules. J Biol Chem 289:19850-4
Miller, Michael B; Wang, Daphne W; Wang, Fei et al. (2013) Cofactor molecules induce structural transformation during infectious prion formation. Structure 21:2061-8
Walsh, Daniel J; Noble, Geoffrey P; Piro, Justin R et al. (2012) Non-reducing alkaline solubilization and rapid on-column refolding of recombinant prion protein. Prep Biochem Biotechnol 42:77-86
Miller, Michael B; Supattapone, Surachai (2011) Superparamagnetic nanoparticle capture of prions for amplification. J Virol 85:2813-7
Piro, Justin R; Harris, Brent T; Supattapone, Surachai (2011) In situ photodegradation of incorporated polyanion does not alter prion infectivity. PLoS Pathog 7:e1002001
Piro, Justin R; Supattapone, Surachai (2011) Photodegradation illuminates the role of polyanions in prion infectivity. Prion 5:49-51
Piro, Justin R; Wang, Fei; Walsh, Daniel J et al. (2011) Seeding specificity and ultrastructural characteristics of infectious recombinant prions. Biochemistry 50:7111-6
Miller, Michael B; Geoghegan, James C; Supattapone, Surachai (2011) Dissociation of infectivity from seeding ability in prions with alternate docking mechanism. PLoS Pathog 7:e1002128

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