Despite decades of scientific research and heightening public and governmental anxiety over the potential dangers of infectious proteins and their role in epidemics such as new variant Creutzfeldt-Jacob disease, Mad Cow disease, and chronic Wasting disease, the mechanisms responsible for the conversion of a normal cellular protein into an infectious prion protein continue to defy understanding. The cellular factors instrumental to the protein conformational changes that result in prion formation, as well as those factors necessary for the subsequent stabilization of the altered prion conformation, remain a mystery. Considering that prion formation and inheritance are tightly related to the protein folding machinery, we propose to investigate the link between prion formation and heat shock transcriptional factors (HSFs). HSFs are evolutionally conserved transcriptional factors responsible for the biosynthesis of the majority of molecular chaperones, which are essential for protecting cells from extreme harsh conditions by refolding or dis-aggregating denatured proteins produced during the stress. Several molecular chaperones are also shown to play essential roles in prion propagation. Using the budding yeast Saccharomyces cerevisiae as the model organism, we propose to elucidate the relationship between HSFs and prion formation/propagation. Our long-term goal of the proposed research is to identify protein factors whose functions are regulated by HSFs and are essential for prion formation/propagation.
The specific aims are: 1) to examine the regulatory role of heat shock protein 90kDa (Hsp90) complex in de novo formation and "strain" maintenance of [PSI+];2) to test if HSF and Hsp90 complex regulate other yeast prions. We will investigate if the effects of HSF and Hsp90/cochaperones are [PSI+] specific: 3) to identify additional novel factors that are HSF targets and responsible for prion formation and propagation.

Public Health Relevance

Prion diseases are a group of infectious neurodegenerative diseases also known as transmissible spongiform encephalopathies. The molecular mechanisms govern the etiology of prion diseases are poorly understood. We propose to identify cellular factors that are required for prion conformational conversion and are important for subsequent stabilization of the acquired prion conformation. The success of proposed study will likely provide target genes for future drug discovery and new therapeutics for the devastating prion diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056086-05
Application #
8213745
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wong, May
Project Start
2008-02-01
Project End
2013-07-31
Budget Start
2012-02-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$321,214
Indirect Cost
$106,839
Name
Northwestern University at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Du, Zhiqiang; Li, Liming (2014) Investigating the interactions of yeast prions: [SWI+], [PSI+], and [PIN+]. Genetics 197:685-700
Nussbaum-Krammer, Carmen I; Park, Kyung-Won; Li, Liming et al. (2013) Spreading of a prion domain from cell-to-cell by vesicular transport in Caenorhabditis elegans. PLoS Genet 9:e1003351
Crow, Emily T; Du, Zhiqiang; Li, Liming (2011) A small, glutamine-free domain propagates the [SWI(+)] prion in budding yeast. Mol Cell Biol 31:3436-44
Park, Kyung-Won; Li, Liming (2011) Prion protein in Caenorhabditis elegans: Distinct models of anti-BAX and neuropathology. Prion 5:28-38
Crow, Emily T; Li, Liming (2011) Newly identified prions in budding yeast, and their possible functions. Semin Cell Dev Biol 22:452-9
Hines, Justin K; Li, Xiaomo; Du, Zhiqiang et al. (2011) [SWI], the prion formed by the chromatin remodeling factor Swi1, is highly sensitive to alterations in Hsp70 chaperone system activity. PLoS Genet 7:e1001309
Fushimi, Kazuo; Long, Charles; Jayaram, Neha et al. (2011) Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy. Protein Cell 2:141-9
Zhang, Jianming; Yang, Huyuan; Long, Manyuan et al. (2010) Evolution of enzymatic activities of testis-specific short-chain dehydrogenase/reductase in Drosophila. J Mol Evol 71:241-9
Du, Zhiqiang; Crow, Emily T; Kang, Hyun Seok et al. (2010) Distinct subregions of Swi1 manifest striking differences in prion transmission and SWI/SNF function. Mol Cell Biol 30:4644-55
Park, Kyung-Won; Li, Liming (2008) Cytoplasmic expression of mouse prion protein causes severe toxicity in Caenorhabditis elegans. Biochem Biophys Res Commun 372:697-702

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