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.
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.
|Klimova, Nina; Makarava, Natallia; Baskakov, Ilia V (2015) The diversity and relationship of prion protein self-replicating states. Virus Res 207:113-9|
|Katorcha, Elizaveta; Makarava, Natallia; Savtchenko, Regina et al. (2014) Sialylation of prion protein controls the rate of prion amplification, the cross-species barrier, the ratio of PrPSc glycoform and prion infectivity. PLoS Pathog 10:e1004366|
|Jeffrey, M; McGovern, G; Makarava, N et al. (2014) Pathology of SSLOW, a transmissible and fatal synthetic prion protein disorder, and comparison with naturally occurring classical transmissible spongiform encephalopathies. Neuropathol Appl Neurobiol 40:296-310|
|Baskakov, Ilia V (2014) The many shades of prion strain adaptation. Prion 8:|
|Lee, Young Jin; Baskakov, Ilia V (2014) The cellular form of the prion protein guides the differentiation of human embryonic stem cells into neuron-, oligodendrocyte-, and astrocyte-committed lineages. Prion 8:266-75|
|Lee, Young Jin; Baskakov, Ilia V (2013) The cellular form of the prion protein is involved in controlling cell cycle dynamics, self-renewal, and the fate of human embryonic stem cell differentiation. J Neurochem 124:310-22|
|Makarava, Natallia; Savtchenko, Regina; Baskakov, Ilia V (2013) Selective amplification of classical and atypical prions using modified protein misfolding cyclic amplification. J Biol Chem 288:33-41|
|Gonzalez-Montalban, Nuria; Lee, Young Jin; Makarava, Natallia et al. (2013) Changes in prion replication environment cause prion strain mutation. FASEB J 27:3702-10|
|Kovacs, Gabor G; Makarava, Natallia; Savtchenko, Regina et al. (2013) Atypical and classical forms of the disease-associated state of the prion protein exhibit distinct neuronal tropism, deposition patterns, and lesion profiles. Am J Pathol 183:1539-47|
|Makarava, Natallia; Baskakov, Ilia V (2012) Purification and fibrillation of full-length recombinant PrP. Methods Mol Biol 849:33-52|
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