Date of Award

Fall 12-9-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

School

Mathematics and Natural Sciences

Committee Chair

Vijay Rangachari

Committee Chair School

Mathematics and Natural Sciences

Committee Member 2

Jacques Kessl

Committee Member 2 School

Mathematics and Natural Sciences

Committee Member 3

Song Guo

Committee Member 3 School

Mathematics and Natural Sciences

Committee Member 4

Hao Xu

Committee Member 4 School

Biological, Environmental, and Earth Sciences

Committee Member 5

Alex Flynt

Committee Member 5 School

Biological, Environmental, and Earth Sciences

Abstract

Granulins (GRNs) are small, cysteine-rich modules produced from the proteolytic cleavage of the precursor protein called progranulin (PGRN). GRNs are present in the form of seven tandem repeats within the precursor and are known to be produced in the extracellular and in lysosomal environments. In physiology, PGRN and GRNs plays pleiotropic roles such as neuronal growth and differentiation, immunomodulation, wound healing. Recent studies have implicated pathological role for PGRN in Alzheimer disease (AD) and frontotemporal dementia (FTD) but specific mechanism(s) remains unclear. However, potential interactions between GRNs and Ab42 and TDP-43 seem like a plausible underlying mechanism. Studies presented here are focused on uncovering these mechanisms by investigating the interactions between GRN-2,-3 and -5 and the C-terminal, prion-like, domain of TDP-43, termed PrLD (CHAPTERS II and III), and between GRN-3 with Ab42 (CHAPTER IV). The results suggest that GRNs differentially modulate the phase behavior and aggregation of TDP-43 PrLD depending on a balance of electrostatic forces and redox state of the former. In addition, GRN-3 in both redox states promoted amyloid fibrils of Ab42 establishing that promoting toxic amyloid aggregates as a potential mechanism for GRNs. Finally, results presented in the fifth chapter reveal a previously unknown physiological role for GRNs as selective Cu sequestering proteins. Overall, these investigations bring out new pathophysiological characteristics of GRNs that have remained unknown thus far, and open doors to furthering these investigations toward potential therapeutic or diagnostic application for neurodegenerative diseases.

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