Date of Award

Fall 12-2023

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

Faqing Huang

Committee Member 2 School

Mathematics and Natural Sciences

Committee Member 3

Jacques Kessl

Committee Member 3 School

Mathematics and Natural Sciences

Committee Member 4

Sarah Morgan

Committee Member 4 School

Polymer Science and Engineering

Committee Member 5

Hao Xu

Committee Member 5 School

Biological, Environmental, and Earth Sciences

Abstract

Amyloid aggregates of specific proteins form important pathological hallmarks in many neurodegenerative diseases, defining neuronal degeneration and disease onset. Recently, increasing numbers of patients show co-morbidities and exhibit clinical and pathological overlaps between multiple neurodegenerative diseases including α-synucleinopathies and TDP-43 proteinopathies. These overlaps are often accompanied by co-localization of α-synuclein (αS) and TDP-43 enhancing the possibility of direct interactions to generate heterotypic amyloids with distinct cellular consequences. To understand this, we investigate the interaction of α-synuclein (αS) and prion-like domain of TDP-43 (TDP-43 PrLD) in both homogenous and inhomogeneous phases. Firstly, we show that monomeric TDP-43 PrLD and αS interact synergistically to generate neurotoxic hybrid fibrils. Interestingly, we also show that both αS oligomers and fibrils cross-seed TDP-43 PrLD monomers, whereas TDP-43 PrLD fibrils do not cross-seed αS monomers. Both monomeric and fibrillar αS also induces the formation of polymorphic TDP-43 PrLD heterotypic fibrils with enhanced neurotoxicity and ability to induce synaptic dysfunction. In inhomogeneous phases, we show that αS acts as a Pickering agent by forming cluster on the surface of TDP-43 PrLD ­– RNA droplets, prevents the coalescence and nucleate TDP-43 PrLD aggregation to form heterotypic amyloids. Finally, we also show that the both DOPAL and DHA-derived αS oligomers cross-seeds Aβ to form neurotoxic fibrils showing the molecular basis of the interplay between Alzheimer’s and Parkinson’s disease. Overall, this study brings forth insights into αS and TDP-43 interactions to better understand the molecular basis of overlapping clinical and pathological presentation in neurodegenerative co-pathologies.

ORCID ID

0000-0003-0019-803X

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