Certain neurodegenerative diseases, such as sheep scrapie, mad cow disease and Creutzfeldt-Jacob disease in humans, appear to be transmitted by an infectious protein, called a prion, without any nucleic acid. The prion, is proposed to be an altered form of a cellular protein which can convert the normal protein (PrPC) into its prion PrPSc) conformation. Recent evidence indicates what prions are not limited to the well characterized mammalian case, but that two yeast proteins can also take on self- propagating """"""""prion"""""""" conformations. Thus, genetic variability operating solely at the level of protein conformation may be a widely used mechanism of inheritance. Yeast is an ideal organism in which to investigate the basics of the prion form of inheritance. Thus, detailed genetic and biochemical studies of the yeast [PSI+] factor, which is a prion form of the Sup35p=eukaryotic release factor eRF3), are proposed. The existence of different scrapie strains, which are suggestive of mutations in viral nucleic acid, has challenged the prion hypothesis. Analogous variants of the yeast [PSI+] prion, that could not have been caused by viruses, have recently been obtained for this study, supporting the view that different prion strains correspond to distinct self- propagating prion protein conformations. The [ETA+] factor, previously discovered by the PI, will be investigated to determine whether it is a new prion or a variant of the [PSI+] prion. Suggestive evidence for the existence of different functional (i.e. [psi-]) conformations of Sup35p, some of which are also self-propagating prions, will be explored. The biochemical properties of all [PSI+] and [psi-] variants and the rules that govern their inheritance and genetic interactions will be defined. Similar genetic analyses of mammalian prion strains would be much more difficult. A structure/function analysis of the [PSI] prion protein, Sup35p, will also be undertaken. Small peptides of Sup35p that can and cannot induce [PSI+], will be obtained to mark regions of Sup35p involved in [PSI+] induction and maintenance. Mutations in SUP35 will be obtained that stimulate the spontaneous appearance of [PSI+] and are therefore analogous to """"""""familial"""""""" mutations in the mammalian prion gene. The mammalian familial mutations appear to increase the inclination of normally folded PrPC protein to flip into the prion conformation, thereby causing the prion disease. New alleles of SUP35 that prevent the Sup35 protein from becoming [PSI+] in the presence of absence of [PSI+] """"""""seeds"""""""" will also be obtained and characterized. Finally, new genes that affect the induction or propagation of the [PSI+] prion will be identified and several genes known to interact with SUP35 will be specifically tested for their effects on [PSI+].

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056350-03
Application #
6019337
Study Section
Genetics Study Section (GEN)
Program Officer
Anderson, James J
Project Start
1997-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Newby, Gregory A; Kiriakov, Szilvia; Hallacli, Erinc et al. (2017) A Genetic Tool to Track Protein Aggregates and Control Prion Inheritance. Cell 171:966-979.e18
Park, Sei-Kyoung; Hong, Joo Y; Arslan, Fatih et al. (2017) Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis. PLoS Genet 13:e1006805
Arslan, Fatih; Hong, Joo Y; Kanneganti, Vydehi et al. (2015) Heterologous aggregates promote de novo prion appearance via more than one mechanism. PLoS Genet 11:e1004814
Yang, Zi; Stone, David E; Liebman, Susan W (2014) Prion-promoted phosphorylation of heterologous amyloid is coupled with ubiquitin-proteasome system inhibition and toxicity. Mol Microbiol 93:1043-56
Yang, Zi; Hong, Joo Y; Derkatch, Irina L et al. (2013) Heterologous gln/asn-rich proteins impede the propagation of yeast prions by altering chaperone availability. PLoS Genet 9:e1003236
Derkatch, Irina L; Liebman, Susan W (2013) The story of stolen chaperones: how overexpression of Q/N proteins cures yeast prions. Prion 7:294-300
Sharma, Jaya; Liebman, Susan W (2013) Exploring the basis of [PIN(+)] variant differences in [PSI(+)] induction. J Mol Biol 425:3046-59
Sharma, Jaya; Liebman, Susan W (2012) [PSI(+) ] prion variant establishment in yeast. Mol Microbiol 86:866-81
Liebman, Susan W; Chernoff, Yury O (2012) Prions in yeast. Genetics 191:1041-72

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