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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS046478-05
Application #
7509929
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wong, May
Project Start
2003-07-01
Project End
2013-04-30
Budget Start
2008-05-15
Budget End
2009-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$314,803
Indirect Cost
Name
Dartmouth College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Zhao, Yanding; Zurawel, Ashley A; Jenkins, Nicole P et al. (2018) Comparative Analysis of Mutant Huntingtin Binding Partners in Yeast Species. Sci Rep 8:9554
Noble, Geoffrey P; Dolph, Patrick J; Supattapone, Surachai (2016) Interallelic Transcriptional Enhancement as an in Vivo Measure of Transvection in Drosophila melanogaster. G3 (Bethesda) 6:3139-3148
Zurawel, Ashley A; Kabeche, Ruth; DiGregorio, Sonja E et al. (2016) CAG Expansions Are Genetically Stable and Form Nontoxic Aggregates in Cells Lacking Endogenous Polyglutamine Proteins. MBio 7:
Noble, Geoffrey P; Supattapone, Surachai (2015) Dissociation of recombinant prion autocatalysis from infectivity. Prion 9:405-11
Supattapone, Surachai (2015) Expanding the prion disease repertoire. Proc Natl Acad Sci U S A 112:11748-9
Noble, Geoffrey P; Wang, Daphne W; Walsh, Daniel J et al. (2015) A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers. PLoS Pathog 11:e1005017
Noble, Geoffrey P; Walsh, Daniel J; Miller, Michael B et al. (2015) Requirements for mutant and wild-type prion protein misfolding in vitro. Biochemistry 54:1180-7
Supattapone, Surachai (2014) Elucidating the role of cofactors in mammalian prion propagation. Prion 8:100-5
Supattapone, Surachai (2014) Synthesis of high titer infectious prions with cofactor molecules. J Biol Chem 289:19850-4
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

Showing the most recent 10 out of 48 publications