Advisor(s)
Andrew Arrant
Committee Member(s)
Erik Roberson
Lucas Pozzo-Miller
Rita Cowell
Sami Barmada
Talene Yacoubian
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Neurobiology
Date of Award
9-11-2025
Abstract
Frontotemporal dementia (FTD) is a major cause of early onset dementia, primarily presenting with behavioral changes or language impairments. The two most common proteins that aggregate in FTD are tau and TDP-43. This dissertation focuses on TDP-43 pathology, which is primarily characterized by loss of nuclear TDP-43 and its cytoplasmic accumulation, and nuclear and cytoplasmic TDP-43 aggregates. Most FTD cases are sporadic, but FTD is a highly genetic disease and around 25% of cases are due to inherited mutations. Heterozygous mutations in the progranulin gene (GRN) cause haploinsufficiency of the progranulin protein and are an autosomal dominant cause of familial FTD (FTD-GRN). It is not known how GRN mutations result in FTD with TDP-43 pathology. Progranulin is known to promote neuron outgrowth, suppress inflammation, and maintain lysosomal function. Grn+/– and Grn–/– mice are used to model FTD-GRN and identify mechanisms that may cause disease. Both Grn+/– and Grn–/– mice have some behavioral changes that model FTD-GRN, notably a low social dominance phenotype in Grn+/– mice. However, Grn+/– mice do not develop TDP-43 pathology or other pathologic hallmarks of FTD-GRN. Grn–/– mice develop lysosomal dysfunction and inflammation that is seen in FTD-GRN but only develop sparse TDP-43 aggregates in the thalamus at advanced ages. To investigate how progranulin insufficiency may influence phenotypes in a more robust model of TDP-43 pathology, we have crossed the progranulin insufficient mice with a human TDP-43 overexpressing mouse line. In the following chapters, I will lay out our current understanding of progranulin and TDP-43 in FTD. I will also describe my experiments investigating how progranulin insufficiency and TDP-43 overexpression influence behavioral and pathologic hallmarks of FTD-GRN, and the potential mechanisms underlying these changes. Taken together, these data provide interesting insights into how progranulin insufficiency can influence TDP-43 and has implications for the treatment of FTD-GRN patients.
ProQuest ID
Recommended Citation
Cook, Anna, "Interactions Between Progranulin Insufficiency And Tdp-43 Overexpression In A Mouse Model Of Frontotemporal Dementia" (2025). All ETDs from UAB. 7347.
https://digitalcommons.library.uab.edu/etd-collection/7347
