All ETDs from UAB

Advisory Committee Chair

Shaida A Andrabi

Advisory Committee Members

Lori L McMahon

Charles F Falany

Andrew B West

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Transactivation response element (TAR) DNA binding protein of 43 kDa (TDP-43) is an essential RNA-binding protein required for coordinating multiple aspects of RNA metabolism. TDP-43 is multifunctional in both nuclear and cytoplasmic cellular compartments and shuttling in and out of the nucleus is an integral part of TDP-43 function. Nuclear depletion and cytoplasmic accumulation of TDP-43, aggregation of TDP-43 within inclusion bodies in the cytoplasm, and aberrant post-translational modifications and truncation of TDP-43 are all common pathological features of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). Localization of TDP-43 is connected to essential functions such as alternative splicing regulation and microRNA processing, and ultimately, loss of TDP-43 function contributes to cell death. TDP-43 pathology is present in 97% of ALS patients, yet a clear understanding of how pathological features of TDP-43 found in neurodegenerative disease are cytotoxic remain unknown. This is due in part to a lack of understanding of how compartmentalization and trafficking of TDP-43 throughout the cell is regulated. In this dissertation, I outline novel findings in the mechanism of regulated transport of TDP-43 from the nucleus to the cytoplasm under cell stress conditions that model neurodegeneration. I investigate two pathways that influence TDP-43 localization. One involves hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) as a DNA damage response pathway that contributes to neurodegeneration. The other is a nuclear export pathway involving the nuclear transport receptor exportin-1 (XPO1). This dissertation describes a novel mechanism where XPO1, which does not participate in nuclear export of TDP-43 under healthy conditions, becomes the dominant nuclear export pathway for TDP-43 in cell stress conditions where PARP1 is hyperactivated. These finds provide support and rationale for investigating clinically approved PARP1 and XPO1 inhibitors for the treatment of neurodegenerative diseases with TDP-43 pathology.



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