A conserved mechanism of gene regulation during stress is the phase separation of mRNA and proteins into membrane-less compartments termed messenger ribonucleoprotein (mRNP) granules. Recent research has implicated aberrant formation of these granules in the pathology of a variety of neurodegenerative diseases. It has been proposed that mislocalization of mRNAs and proteins to these pathological inclusions can cause a toxic gain-of-function through altered gene expression control. Our research program aims to use the formation of mRNP granules during glucose starvation in yeast to elucidate basic mechanistic principles about the formation and function of these membrane-less compartments as well as to apply the knowledge and technical expertise from yeast to understand how phase separation of RNA-binding proteins associated with neurodegenerative diseases impinge upon gene expression in mammalian cells. This research builds on our discovery that during stress, transcription and translation can be coupled, as promoter elements can determine the localization of mRNAs to mRNP granules, thereby impinging on their subsequent translatability. Our strategy will take a two-part approach. The first direction will focus on elucidating the mechanism by which promoter elements in the nucleus can direct the localization of mRNAs to mRNP granules in the cytoplasm. Second, we will explore the function that this differential localization has on the gene expression of yeast and mammalian cells. This research will give insight into basic questions of what specifies mRNA localization to membrane-less compartments and how this affects the gene expression of the cell, which is important for understanding the effects that toxic mRNP aggregates may have on cells during neurodegeneration.

Public Health Relevance

It has recently emerged that in a number of debilitating neurodegenerative diseases RNAs and proteins become mislocalized to pathological aggregates. The proposed research will explore the mechanism by which RNAs can be selectively localized to RNA/protein aggregates as well as the effects this has on protein expression in the cell. In the long term this research may give us greater understanding of the formation and function of these toxic aggregates during neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
3R35GM128798-03S1
Application #
10156025
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Gaillard, Shawn R
Project Start
2018-07-25
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093