All ETDs from UAB

Advisory Committee Chair

Shaida A Andrabi

Advisory Committee Members

Lori L McMahon

Charles F Falany

Andrew B West

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

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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