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.
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
Recommended Citation
Oldani, Emily Grace, "Biophysical Characterization of the ALS-Linked Protein TDP-43; and Genetic and Small Molecule Rescues from Its Cytotoxicity" (2024). Electronic Theses and Dissertations. 2385.
https://digitalcommons.du.edu/etd/2385