Publication Date

2018-11-07

Availability

Open access

Embargo Period

2018-11-07

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2018-10-26

First Committee Member

Stephen Lee

Second Committee Member

Feng Gong

Third Committee Member

Sapna Deo

Fourth Committee Member

Daniel G. Isom

Fifth Committee Member

Kerry L. Burnstein

Sixth Committee Member

Karim Mekhail

Abstract

Phase transitions of matter between gas, condensed liquid and solid states are ubiquitous in the physical world. Recent discoveries have shown that a dynamic continuum of material states also exists within the cellular environment. Whereas examples of mobile, liquid-like droplets are found throughout the cell, such as nucleoli and stress granules, examples of immobile, solid-like amyloid structures have largely been associated with pathological aggregates, and are considered the result of an aberrant liquid-to-solid phase transition. Here, we demonstrate stress-induced low complexity RNA activate a physiological liquid-to-solid phase transition to form solid-like Amyloid bodies (A-bodies). A-bodies are membrane-less compartments that can be distinguished from other structures as they display properties associated with immobile, solid-like amyloids. The biological role of A-bodies is to promote cellular dormancy under stress conditions such as heat shock or extracellular acidosis. The notion that molecules can adopt different states of matter to perform various functions represents a conceptual advance in our understanding of cellular organization. This work also highlights the importance of low complexity RNA in constructing membrane-less compartments in a cell, adding to the list of architectural determinants that confer membrane-less compartments their unique identities. Broadly, the data suggest we reassess 1) the perception that amyloids as exclusively toxic and 2) the importance of different simple repeats commonly observed throughout the genome and often dismissed as junk. We hope the knowledge gained from the study of A-bodies will offer alternative insights into how we understand and treat diseases related to age, neurodegeneration as well as cancer.

Keywords

amyloidogenesis; beta-amyloid; rDNA intergenic spacer; liquid-to-solid phase transition; phase separation; architectural RNA; junk DNA; complex coacervation; self-assembly

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