Date of Award

Summer 8-22-2026

Document Type

Dissertation

Degree Name

Ph.D. in Chemistry and Biochemistry

Organizational Unit

College of Natural Science and Mathematics, Chemistry and Biochemistry

First Advisor

Scott Horowitz

Second Advisor

Sunil Kumar

Third Advisor

Allegra Aron

Fourth Advisor

Todd Wells

Fifth Advisor

Daniel Linseman

Copyright Statement / License for Reuse

All Rights Reserved
All Rights Reserved.

Keywords

Amyotrophic lateral sclerosis (ALS), Treatment, C. elegans, Aggregation

Abstract

Neurodegenerative diseases (NDs) are progressive disorders characterized by neuronal loss, and their prevalence is rising with an aging global population. Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which TDP-43 protein forms toxic aggregates in more than 95% of cases. Current FDA-approved ALS treatments do not target TDP-43 aggregation directly and extend survival by only months. There is, therefore, a pressing need for therapeutic interventions that act at the molecular level of TDP-43 pathology. Here, we tested two different approaches via C. elegans expressing human TDP-43 protein in neurons using either direct or indirect mechanisms to modulate TDP-43 aggregation. To directly inhibit TDP-43 aggregation, we tested two Oligopyridylamide (OP) ligands that were shown to directly bind TDP-43 and prevent its aggregation in vitro. Treating the worms with these OPs prevented TDP-43 inclusion formation in neurons and the development of neurological symptoms. In addition to aggregating, TDP-43 is also known to bind a nucleic acid secondary structure known as G-quadruplex (G4) structure, which has been shown previously to be a powerful modulator of protein aggregation. To indirectly modulate TDP-43 aggregation through G4 structures, we ligated Protoporphyrin IX (PPIX), a well-characterized G4-binder, to a PROTAC group to target G4-TDP-43 complex for proteasomal degradation. Worms treated with PPIX-PROTAC showed a decrease in the TDP-43 inclusion formation, ameliorating the neurological symptoms. These results show that both direct and indirect aggregation prevention are possible avenues to pursue for TDP-43 lead therapeutics.

Copyright Date

8-2026

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Eman Elshaalia

Provenance

Received from ProQuest

File Format

application/pdf

Language

English (eng)

Extent

144 pgs

File Size

15.5 MB

Download

Available for download on Friday, September 24, 2027



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