Date of Award
2026
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Interdisciplinary Neuroscience
Department
Cell & Molecular Biology
First Advisor
Claudia Fallini
Abstract
Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a progressive neurodegenerative disease spectrum characterized by motor dysfunction, cognitive decline, and death within a few years of clinical onset. Hallmark features of ALS/FTD include defects in nucleocytoplasmic transport (NCT) and abnormal cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43, both of which have been shown to be exasperated by oxidative stress (OS). It remains unclear how these processes are connected and how they collectively contribute to neurodegeneration. To fill this gap of knowledge, we used human embryonic kidney cells, neuroblastoma cells, and induced pluripotent stem cell-derived cortical neurons harboring the ALS/FTD C9ORF72 mutation to investigate the role of OS on nucleopore complex (NPC) integrity, Ran-mediated NCT, and TDP-43 localization. Through immunofluorescence imaging, we identified more pronounced NPC and NCT responses to OS, along with transient TDP-43 redistribution in post-mitotic neurons compared to mitotic cells. We further found neuronal maturation and patient genetic background to be important modulators of the OS response, where more mature neurons displayed persistent cytoplasmic relocalization of TDP-43 following stress recovery and mutant neurons often exhibited greater variability in stress responses across individual lines. Additionally, TDP-43 localization was not strictly dependent on Ran-mediated NCT, as OS induced a partial decoupling between TDP-43 and Ran distribution. Overall, these findings demonstrate that responses to OS are shaped by intrinsic cellular properties and genetic variability, and suggest that the loss of TDP-43 homeostasis over time may contribute to downstream NCT alterations in ALS/FTD pathology.
Recommended Citation
Collins, Alicia Christine, "INVESTIGATING THE EFFECTS OF NUCLEOPORE DEFECTS ON THE CELLULAR RESPONSE TO STRESS IN ALS/FTD IPSC-DERIVED NEURONS" (2026). Open Access Dissertations. Paper 4587.
https://digitalcommons.uri.edu/oa_diss/4587