Prions are self-perpetuating protein isoforms that cause fatal neurodegenerative diseases in mammals and humans and control heritable traits in yeast. Most prions known to date form highly ordered fibrous polymers (amyloids), resembling aggregates involved in non-transmissible amyloidoses, such as Alzheimer's and Parkinson's diseases, or in polyglutamine disorders such as Huntington's disease. Mechanisms of clearance of the amyloid proteins are poorly understood. It is shown by us and other groups that prion propagation in yeast occurs via subsequent cycles of polymer fragmentation and growth, mediated by chaperone proteins. Accumulation of the large cytologically detectable aggregated structures (inclusion bodies) of prion proteins or other amyloidogenic proteins is observed in yeast in certain conditions and is sometimes associated with cytotoxicity. It is demonstrated by our data that some inclusion bodies interact with actin cytoskeletal networks, involved in endocytosis and trafficking of the endocytic vesicles to the vacuole. It is proposed that: 1) inclusion bodies represent intermediates in the prion generation or prion elimination pathways, and 2) prion propagation is regulated by a dynamic equilibrium between the actively proliferating prion units and inclusion bodies incapable of efficient propagation. Chaperones, proteolytic systems, cytoskeletal networks and trafficking pathways modulate prion propagation and clearance by shifting the equilibrium between inclusion bodies and proliferating prion units. Our proposal for the next budget period is designed to test specific predictions based on this general model.
Specific aims of the project will specifically address the roles of chaperones, proteolytic pathways, cytoskeletal networks and intracellular trafficking pathways in generation and clearance of the prion protein aggregates. Taken together, the results of these experiments will uncover the mechanism of clearance of aggregated amyloidogenic proteins in yeast cells Relevance to public health: Mammalian prion diseases and many other amyloidoses are fatal and incurable. Mammalian prion diseases, such as """"""""mad cow"""""""" disease and chronic wasting disease of elk and deer, represent a significant health threat due to a possibility of their transmission to humans with infected meat. Some amyloid diseases, such as Alzheimer's disease, are widespread and age-dependent, so that their importance is going to grow further in parallel with the eradication of other diseases and improvement of the average life span of human populations. This research will further establish yeast as a model for development of the strategies counteracting accumulation and propagation of prions and other toxic amyloids.
| Gong, He; Romanova, Nina V; Allen, Kim D et al. (2012) Polyglutamine toxicity is controlled by prion composition and gene dosage in yeast. PLoS Genet 8:e1002634 |
| Antony, H; Wiegmans, A P; Wei, M Q et al. (2012) Potential roles for prions and protein-only inheritance in cancer. Cancer Metastasis Rev 31:1-19 |
| Kiktev, Denis A; Patterson, Jesse C; Muller, Susanne et al. (2012) Regulation of chaperone effects on a yeast prion by cochaperone Sgt2. Mol Cell Biol 32:4960-70 |
| Liebman, Susan W; Chernoff, Yury O (2012) Prions in yeast. Genetics 191:1041-72 |
| Chernova, Tatiana A; Romanyuk, Andrey V; Karpova, Tatiana S et al. (2011) Prion induction by the short-lived, stress-induced protein Lsb2 is regulated by ubiquitination and association with the actin cytoskeleton. Mol Cell 43:242-52 |
| Newnam, Gary P; Birchmore, Jennifer L; Chernoff, Yury O (2011) Destabilization and recovery of a yeast prion after mild heat shock. J Mol Biol 408:432-48 |
| Kiktev, D A; Chernoff, Y O; Archipenko, A V et al. (2011) Identification of genes influencing synthetic lethality of genetic and epigenetic alterations in translation termination factors in yeast. Dokl Biochem Biophys 438:117-9 |
| Chen, Buxin; Bruce, Kathryn L; Newnam, Gary P et al. (2010) Genetic and epigenetic control of the efficiency and fidelity of cross-species prion transmission. Mol Microbiol 76:1483-99 |
| Goehler, Heike; Droge, Anja; Lurz, Rudi et al. (2010) Pathogenic polyglutamine tracts are potent inducers of spontaneous Sup35 and Rnq1 amyloidogenesis. PLoS One 5:e9642 |
| Romanova, Nina V; Chernoff, Yury O (2009) Hsp104 and prion propagation. Protein Pept Lett 16:598-605 |
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