Biophysical Characterization of the ALS-Linked Protein TDP-43; and Genetic and Small Molecule Rescues from Its Cytotoxicity

Date of Award

6-15-2024

Document Type

Dissertation

Degree Name

Ph.D.

Organizational Unit

College of Natural Science and Mathematics, Chemistry and Biochemistry

First Advisor

Sunil Kumar

Second Advisor

Martin Margittai

Third Advisor

Schuyler van Engelenberg

Fourth Advisor

Scott Barbee

Keywords

Structural biology, Aggregation prone proteins, Amyotrophic lateral sclerosis (ALS), Protein-RNA interactions, Protein-protein interactions, TDP-43

Abstract

Human trans-active response DNA binding protein 43 kDa (hTDP-43) is a protein necessary to the trafficking and processing of messenger ribonucleic acids (mRNA) in human cells but is also aggregation prone and has been implicated in amyotrophic lateral sclerosis (ALS). The structure of this multi-domain protein remains unknown, as each domain is linked by a disordered linker region. The C-terminal domain (CTD) is largely disordered, and the protein is 43 kDa and thus too large for many imaging techniques. hTDP-43 has been observed, both in vivo and in vitro, to form a native homodimer, but the precise interface of dimerization is unknown. The mechanism of aggregation is also unknown. As ALS is a disease currently without cure, anti-aggregation and dis-aggregase therapeutics are needed. This thesis sought to probe the structure of hTDP-43 with a battery of techniques to determine the structure of full-length hTDP-43 as well as to identify putative therapeutics to combat the aggregation of hTDP-43.

Copyright Date

6-2024

Copyright Statement / License for Reuse

All Rights Reserved
All Rights Reserved.

Publication Statement

Copyright is held by the author. Permanently suppressed.

Rights Holder

Emily Grace Oldani

Provenance

Received from author

File Format

application/pdf

Language

English (eng)

Extent

279 pgs

File Size

21.9 MB

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