Date of Award
Summer 8-3-2026
Document Type
Dissertation
Publication Status
Version of Record
Submission Date
August 2026
Department
Biological Sciences
College Granting Degree
Charles E. Schmidt College of Science
Department Granting Degree
Biological Sciences
Degree Name
Doctor of Philosophy (PhD)
Thesis/Dissertation Advisor [Chair]
Jianning Wei
Abstract
Neuroinflammation is a well-established component of Huntington's disease (HD) pathogenesis, yet the intricate molecular mechanisms that govern this process remain a topic of ongoing research and debate. This dissertation elucidates a novel pathway linking arginine metabolism and nitrosative stress to core HD pathology. We found that the arginine transporter SLC7A2 is selectively upregulated in various HD cellular models and patient samples. Our findings reveal that this upregulation drives an overactive inflammatory response, leading to abnormally high inducible nitric oxide synthase (iNOS) induction and subsequent nitric oxide (NO) production, which causes excessive protein nitrosylation and an increase in mitochondrial fragmentation.
To further characterize the broad transcriptomic changes underlying this phenomenon, we employed RNA sequencing (RNA-seq) and bioinformatic analysis. This analysis revealed a pronounced and more robust inflammatory response in mutant Huntingtin cells, with a greater number of differentially expressed genes compared to controls, providing comprehensive support for the molecular pathway identified in our initial studies. Our work also found that arginine supplements may potentially accelerate HD progression, a critical observation supported by our analysis of the Enroll-HD human patient dataset. Finally, we utilized microelectrode arrays to investigate the electrophysiological phenotypes of human iPSC-derived HD neurons undergoing nitrosative stress as an experimental pilot study to build a framework for future functional analysis.
Recommended Citation
Gaudet, Ian D., "CONTRIBUTIONS OF ARGININE AND NITROSATIVE STRESS TO HUNTINGTON’S DISEASE PROGRESSION" (2026). Electronic Theses and Dissertations. 406.
https://digitalcommons.fau.edu/etd_general/406