Advisor(s)
Rita Cowell
Committee Member(s)
Jeremy Day
Matthew Alexander
School
Joint Health Sciences (Interdisciplinary)
Document Type
Thesis
Department (new version)
Joint Health Sciences
Date of Award
9-11-2025
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping pathology, such as TDP-43 protein aggregation. Studies in ALS-FTD patients and TDP-43 overexpression model found an increase in several lysosomal genes, proteins, and storage material, suggesting lysosomes are unable to degrade effectively. As TDP-43 aggregation contributes to autophagy-lysosomal dysregulation through a positive feedback cycle further exacerbating neuronal dysfunction, it is essential to understand what drives autophagy-lysosomal dysregulation by exploring the biological process of lysosomal regulation in neurons. Thus, this study aims at identifying the key regulator of lysosomal maintenance and gene expression in neurons. Past studies explored the microphthalmia transcription factor (MiT/TFE) family in vitro in non-neuronal populations as the master regulator of lysosomal gene expression; however, it is unclear how this family regulates lysosomal gene expression and function in vivo in neuronal populations. Single-cell transcriptomic data by proteinatlas.org and Dropviz.org suggests an understudied MiT/TFE member known as TFE3 is likely to be the most highly expressed member in neurons, and thus, we hypothesized it to be the key mediator of lysosomal regulation in neurons. Comparison of MiT/TFE family member (TFEB, MITF, and TFE3) expression in wildtype mice found that TFE3 is highly abundant in the cortex and hippocampus, regions vulnerable in ALS/FTD. Moreover, TFE3 is significantly more expressed than TFEB and MITF in cortical glutamatergic neurons, suggesting TFE3 may be the best possible MiT/TFE candidate to target in neurons. TFE3’s role in lysosomal maintenance and gene expression was explored with a whole body Tfe3 knockout (Tfe3 KO) mouse model. Protein markers for lysosomal quantity (LAMP1/LAMP2a), function (CTSD) and autophagy (LC3 A/B) were not reduced in hippocampal tissue homogenates and in single-cell cortical neurons. These findings suggest that at baseline conditions, TFE3 is dispensable for maintenance of lysosomal number and gene expression, possibly being compensated by another MiT/TFE member (MITF) when TFE3 is depleted. Stress conditions may be required to evaluate TFE3-mediated transcriptional regulation in Tfe3 KO x TAR44 mouse model. Future studies will explore effects of TFE3 translocation in TDP-43 proteinopathy, with the goal of determining whether it would be a good candidate for therapeutic targeting.
ProQuest ID
Recommended Citation
Siddiqi, Humna, "Exploring The Biological Role Of Tfe3 Regulation In Neurons" (2025). All ETDs from UAB. 7384.
https://digitalcommons.library.uab.edu/etd-collection/7384
