Advisor(s)
Jun Zhang
Committee Member(s)
Aaron Lucius
Elizabeth Duran
Document Type
Thesis
Date of Award
6-18-2026
Degree Name
Master of Science (MS)
School
College of Arts and Sciences
Department
Chemistry
Abstract
Alzheimer’s disease (AD) is characterized by extracellular amyloid-beta (AB) aggregation and widespread defects in RNA processing, yet the molecular mechanisms linking proteotoxic stress to splicing dysregulation remain poorly defined. Increasing evidence suggest that disruptions in nuclear organization and biomolecular condensates contribute to vulnerability in AD. The splicing factors U1-70K and SRSF1 are core components of liquid-liquid phase-separated nuclear speckles and exhibit aberrant mislocalization and aggregation in AD, implicating their dysregulation as a key downstream consequence of AB pathology. RNA G-quadruplexes (GQs) are stable secondary RNA structures enriched within transcripts associated with nuclear speckles and RNA-processing machinery. Recent detection of GQ-containing RNAs within amyloid plaques raises the possibility that AB directly engages structured RNA rather than interacting nonspecifically with the transcriptome. However, whether AB selectively recognizes GQ structures, how such interactions influence RNA organization, and how these events contribute to splicing factor mislocalization remain unknown. Rather than acting solely as passive scaffolds, GQs may represent defined RNA targets whose structure, localization, and protein-binding properties are actively remodeled by AB aggregation. We hypothesize that AB directly interacts with GQ-containing RNAs, altering their intracellular distribution, thereby perturbing the phase behavior and recruitment of splicing factors such as U1-70K and SRSF1. Using complementary biophysical approaches, this work investigates the molecular determinants governing AB- GQ interactions, the consequences of AB exposure on GQ organization and RNA localization, and the downstream effects on U1-70K and SRSF1 phase behavior and solubility. By integrating in vitro binding and localization analyses, this thesis delineates how AB-driven RNA remodeling contributes to splicing factor sequestration. Together, these studies define an RNA-centered mechanism by which AB aggregation disrupts nuclear homeostasis, linking proteotoxic stress to splicing dysfunction in AD and providing new insight into how structured RNA elements mediate the pathological crosstalk between protein aggregation and RNA processing.
Keywords
Alzheimer's disease;Amyloid-beta;G-quadruplexes;nuclear speckles;splicing dysregulation;splicing factors
ProQuest ID
Recommended Citation
Lehman, Nathan, "Structural And Biophysical Determinants Of Amyloid-Βeta Interactions With Splicing Factors And Rna G-Quadruplexes" (2026). ETDs from 2020-2029. 158.
https://digitalcommons.library.uab.edu/etd-2020s/158
