Proteins are the biological macromolecules central to most cellular functions. The native structure of protein determines its function and any perturbations such as mutation, changes in pH, macromolecular crowding, oxidative stress, may promote protein misfolding and/or aggregation. Protein misfolding or aggregation can contribute to diseases either through loss of proteins’ critical function or by gain of toxic function. Among the various proteins associated with neurodegeneration, trans-active response (TAR) DNA binding protein 43 (TDP-43) has sparked interest in researchers due to its diverse role in several neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar degeneration (FTLD), Alzheimer’s, Parkinson’s and Huntington’s disease. Most of the reported work on TDP-43 protein have been carried out on truncated version of the protein from prokaryotic source due to difficulty in expressing and purifying the full-length protein. Another protein, amyloid β peptides role in Alzheimer’s disease has been studied in great detail. However, the role posttranslational modifications play in Aβ related toxicity has not been fully explored. In this dissertation, I address these two major gaps as follows: 1) I have successfully purified full-length TDP-43 protein using a eukaryotic source and carried out some physicochemical characterization. Now this full-length protein which is from eukaryotic source can be used to better understand proteins role in health and disease. 2) I explored the physicochemical properties of acetylated Amyloid β peptides including its effects on modulating toxicity in SH-SY5Y cell lines (neuroblastoma) and primary neuronal cultures. This work underscores the importance of posttranslational modification such as acetylation of Aβ peptides on toxicity as well as aggregate morphology which will lead to better drug designs in future.
|Commitee:||Liu, Haiying, Datta, Rupali, Tang, Xiaoqing|
|School:||Michigan Technological University|
|School Location:||United States -- Michigan|
|Source:||DAI-B 81/3(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Molecular biology|
|Keywords:||Amyloid β acetylation, Cytotoxicity, Neurodegenerative diseases, Protein aggregation, Protein purification, TDP-43|
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