The goals of this grant are to understand the assembly, dynamics, and functions of stress granules in the control of gene expression and how aberrant stress granule formation contributes to neurodegenerative diseases. Stress granules are cytoplasmic granules of mRNAs and proteins that form when translation initiation is limiting and assemble in part by interactions between prion-like domains on RNA binding proteins. Stress granules are of importance for two reasons. First, they sequester mRNAs and mRNA binding proteins and play important roles in modulating gene expression and cellular signaling during stress responses. Second, aberrant stress granule accumulation appears to be a causative event in diseases such as Amyotrophic Lateral Sclerosis (ALS), or Frontotemporal lobar degeneration (FTLD). These diseases can be caused by mutations in RNA binding proteins, such as hnRNPA1, which increase stress granule assembly and promote toxic amyloid formation, or by mutations in the AAA-ATPase VCP, which decrease stress granule clearance by autophagy. Given this importance in both normal stress responses and in pathological conditions, an understanding of both normal and pathological stress granule dynamics is critical. We will take advantage of the powerful approaches in yeast cells to understand fundamental aspects of stress granule dynamics and function. We will also apply our knowledge from yeast to understand how pathogenic mutations affect stress granules in mammalian cells. The specific questions addressed in this proposal are: I) What are the composition, dynamics and affects of stress granules in both normal and pathogenic conditions? II) What are molecular mechanisms connecting stress granule assembly with toxic amyloid formation? III) What are the mechanisms by which stress granules are targeted for autophagy? Completion of these aims will reveal fundamental principles of stress granule dynamics and how aberrant stress granules form and contribute to degenerative diseases, which could facilitate the development of new therapies.

Public Health Relevance

This project focuses on understanding the dynamics and functions of stress granules in the control of gene expression and how aberrant stress granule formation contributes to neurodegenerative diseases. The work will reveal how stress granules assemble and disassemble and how aberrant RNP granules that accumulate in neurogenerative disease are formed. A mechanistic understanding of stress granule control may suggest possible therapies for some neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM045443-25
Application #
8687850
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bender, Michael T
Project Start
1991-04-01
Project End
2018-03-31
Budget Start
2014-04-14
Budget End
2015-03-31
Support Year
25
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80303
Jain, Saumya; Wheeler, Joshua R; Walters, Robert W et al. (2016) ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 164:487-98
Protter, David S W; Parker, Roy (2016) Principles and Properties of Stress Granules. Trends Cell Biol 26:668-79
Shukla, Siddharth; Parker, Roy (2016) Hypo- and Hyper-Assembly Diseases of RNA-Protein Complexes. Trends Mol Med 22:615-28
Shukla, Siddharth; Schmidt, Jens C; Goldfarb, Katherine C et al. (2016) Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects. Nat Struct Mol Biol 23:286-92
Walters, Robert W; Muhlrad, Denise; Garcia, Jennifer et al. (2015) Differential effects of Ydj1 and Sis1 on Hsp70-mediated clearance of stress granules in Saccharomyces cerevisiae. RNA 21:1660-71
Lin, Yuan; Protter, David S W; Rosen, Michael K et al. (2015) Formation and Maturation of Phase-Separated Liquid Droplets by RNA-Binding Proteins. Mol Cell 60:208-19
Garcia, Jennifer F; Parker, Roy (2015) MS2 coat proteins bound to yeast mRNAs block 5' to 3' degradation and trap mRNA decay products: implications for the localization of mRNAs by MS2-MCP system. RNA 21:1393-5
Walters, Robert W; Parker, Roy (2015) Coupling of Ribostasis and Proteostasis: Hsp70 Proteins in mRNA Metabolism. Trends Biochem Sci 40:552-9
Sudhakaran, Indulekha P; Hillebrand, Jens; Dervan, Adrian et al. (2014) FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control. Proc Natl Acad Sci U S A 111:E99-E108
Mitchell, Sarah F; Parker, Roy (2014) Principles and properties of eukaryotic mRNPs. Mol Cell 54:547-58

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