Prion diseases are a group of fatal age-dependent neurodegenerative diseases that can arise spontaneously or be inherited, but can also be infectious. The possibility of spontaneous emergence and the pandemic spread of new prion strains and the transmission and adaptation of existing strains to new hosts including humans are of great concern to public health. Little is known about the molecular aspects of how prions originate and evolve in animals and humans or the principles that underlie the evolution of prion strains. Prion strains exhibit a high level of conformational plasticity and are prone to 'mutation'when transmitted to a new host.
Specific Aim 1 will investigate the mechanism of prion genesis and evolution and test the new hypothesis that transmissible prion diseases can be induced by amyloid structures fundamentally different from that of PrPSc.
Specific Aims 2 will take advantage of new models of prion diseases generated in our laboratory for elucidating the pathological events that lead to clinical prion disease and for exploring factors responsible for strain-specific neurotropism.
Specific Aim 3 will elucidate mechanisms responsible for prion strain 'mutations'and adaptation. Specifically, this aim will test whether a change in the co-factor environment of prion replication leads to a stable change in PrPSc properties and new disease phenotypes and (ii) whether changes in the co-factor environment affect the fate of prion adaptation upon crossing the species barrier. This study will take place in the environment of a medical school, will exploit novel experimental models of prion diseases developed by the PI, and will take advantage of collaborations with internationally known experts on prion pathology. When accomplished, the results from this study will lay the groundwork for understanding the mechanisms of genesis and evolution of infectious protein states and transform our understanding of the mechanisms responsible for adaptation and mutation of prion strains.

Public Health Relevance

Prion diseases are a group of fatal age-dependent neurodegenerative diseases that can arise spontaneously or be inherited, and can also be infectious. Little is known about molecular aspects of how prions originate and evolve in animals and humans, or principles that underlie evolution of prion strains. The current project seeks to elucidate molecular mechanisms underlying prion genesis, evolution, their adaptation and mutation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045585-13
Application #
8651948
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wong, May
Project Start
2003-04-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
13
Fiscal Year
2014
Total Cost
$412,453
Indirect Cost
$131,313
Name
University of Maryland Baltimore
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Morales, Rodrigo; Hu, Ping Ping; Duran-Aniotz, Claudia et al. (2016) Strain-dependent profile of misfolded prion protein aggregates. Sci Rep 6:20526
Makarava, Natallia; Savtchenko, Regina; Alexeeva, Irina et al. (2016) New Molecular Insight into Mechanism of Evolution of Mammalian Synthetic Prions. Am J Pathol 186:1006-14
Katorcha, Elizaveta; Srivastava, Saurabh; Klimova, Nina et al. (2016) Sialylation of Glycosylphosphatidylinositol (GPI) Anchors of Mammalian Prions Is Regulated in a Host-, Tissue-, and Cell-specific Manner. J Biol Chem 291:17009-19
Katorcha, Elizaveta; Daus, Martin L; Gonzalez-Montalban, Nuria et al. (2016) Reversible off and on switching of prion infectivity via removing and reinstalling prion sialylation. Sci Rep 6:33119
Srivastava, Saurabh; Makarava, Natallia; Katorcha, Elizaveta et al. (2015) Post-conversion sialylation of prions in lymphoid tissues. Proc Natl Acad Sci U S A 112:E6654-62
Katorcha, Elizaveta; Makarava, Natallia; Savtchenko, Regina et al. (2015) Sialylation of the prion protein glycans controls prion replication rate and glycoform ratio. Sci Rep 5:16912
Katorcha, Elizaveta; Klimova, Nina; Makarava, Natallia et al. (2015) Loss of Cellular Sialidases Does Not Affect the Sialylation Status of the Prion Protein but Increases the Amounts of Its Proteolytic Fragment C1. PLoS One 10:e0143218
Srivastava, Saurabh; Baskakov, Ilia V (2015) Contrasting Effects of Two Lipid Cofactors of Prion Replication on the Conformation of the Prion Protein. PLoS One 10:e0130283
Makarava, Natallia; Savtchenko, Regina; Baskakov, Ilia V (2015) Two alternative pathways for generating transmissible prion disease de novo. Acta Neuropathol Commun 3:69
Martínez, Javier; Sánchez, Rosa; Castellanos, Milagros et al. (2015) PrP charge structure encodes interdomain interactions. Sci Rep 5:13623

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