Date of Award
2025
Type
Thesis
Major
Master of Science
Degree Type
Master of Science in Natural Science
Department
Biology
First Advisor
Dr. Monica Frazier
Second Advisor
Dr. Kerri Taylor
Third Advisor
Dr. Jonathan Meyers
Abstract
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder that leads to the degeneration of motor neurons, which control voluntary muscle movements such as eating, speaking, and breathing. As these neurons are damaged, voluntary movement ceases, leading to a fatal outcome. The survival time of ALS patients varies, ranging from a few months to up to 10 years. Chapter 1 of this thesis provides an overview of ALS, highlighting the role of transactive response DNA-binding protein 43 (TDP-43), a key feature in ALS and other neurodegenerative diseases. The aggregation of TDP-43, particularly due to mutations in the C9orf72 gene, is cytotoxic and contributes to neuronal death, providing a target for therapeutic intervention. Researchers continue to explore ways to halt or slow the progression of ALS, but currently, no cure exists.
Chapter 2 delves into the therapeutic potential of azolium-based compounds, focusing on Riluzole, one of the two FDA-approved drugs for ALS treatment. While riluzole blocks glutamate release to slow disease progression, it does not significantly extend patient survival or alleviate symptoms. There is limited understanding of how riluzole and similar drugs affect TDP-43 aggregation or the specificity of their action in healthy versus ALS-affected cells. This chapter explores alternative therapeutic approaches through novel azolium salts, which may offer a more targeted means of addressing ALS-related cellular dysfunction.
Chapter 3 details the preparation and transfection of TDP-43 into SH-SY5Y (neuroblastoma) and U-2 OS (osteosarcoma) cell lines to model ALS-like cellular conditions. While Western blotting and flow cytometry were initially used to confirm protein overexpression and evaluate cellular responses to TDP-43, technical limitations affected the consistency and reproducibility of these data. As a result, the Western blot and flow cytometry methods and observations have been included in Appendix B as exploratory analyses to guide future studies.
Chapter 4 investigates the efficacy of the aforementioned novel azolium salts in non-transfected and TDP-43-transfected cell lines. These salts were synthesized and tested for biological activity against WI-38 (normal lung fibroblast) and NCI-H1299 (non-small cell lung cancer) cells to determine the efficacy and cytotoxic impacts. The study provides insight into the cytotoxicity of these organic compounds when exposed to normal and ALS-like cells, in hopes of establishing a structure-activity relationship (SAR) to better understand the impact of different substituent groups and azolium types on the salts' therapeutic potential.
Chapter 5 discusses the broader implications of these findings for future research and therapeutic development. It highlights how these novel azolium salts could contribute to the development of targeted treatments for ALS and other neurodegenerative diseases, to ultimately help advance the understanding of TDP-43 aggregation and its role in disease progression
Recommended Citation
Kennedy, Alisha R., "Targeting ALS: A Multi-Cellular Study on the Potential Therapeutic Role of Azole-Based Compounds" (2025). Theses and Dissertations. 571.
https://csuepress.columbusstate.edu/theses_dissertations/571
