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)
Type
Research Project (R01)
Project #
2R01GM045443-25
Application #
8687850
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bender, Michael T
Project Start
Project End
Budget Start
Budget End
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
Shukla, Siddharth; Parker, Roy (2014) Quality control of assembly-defective U1 snRNAs by decapping and 5'-to-3' exonucleolytic digestion. Proc Natl Acad Sci U S A 111:E3277-86
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
Walters, Robert W; Shumilin, Igor A; Yoon, Je-Hyun et al. (2014) Edc3 function in yeast and mammals is modulated by interaction with NAD-related compounds. G3 (Bethesda) 4:613-22
Mitchell, Sarah F; Parker, Roy (2014) Principles and properties of eukaryotic mRNPs. Mol Cell 54:547-58
Ramaswami, Mani; Taylor, J Paul; Parker, Roy (2013) Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154:727-36
Swisher, Kylie D; Parker, Roy (2011) Interactions between Upf1 and the decapping factors Edc3 and Pat1 in Saccharomyces cerevisiae. PLoS One 6:e26547
Brengues, Muriel; Parker, Roy (2007) Accumulation of polyadenylated mRNA, Pab1p, eIF4E, and eIF4G with P-bodies in Saccharomyces cerevisiae. Mol Biol Cell 18:2592-602
Doma, Meenakshi K; Parker, Roy (2007) RNA quality control in eukaryotes. Cell 131:660-8
Beckham, Carla J; Light, Heather R; Nissan, T Amar et al. (2007) Interactions between brome mosaic virus RNAs and cytoplasmic processing bodies. J Virol 81:9759-68
She, Meipei; Decker, Carolyn J; Sundramurthy, Kumar et al. (2004) Crystal structure of Dcp1p and its functional implications in mRNA decapping. Nat Struct Mol Biol 11:249-56

Showing the most recent 10 out of 37 publications