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
Recommended Citation
Dhakal, Shailendra, "HETEROTYPIC INTERACTION OF α-SYNUCLEIN AND TDP-43 IN NEURODEGENERATIVE DISEASES" (2023). Dissertations. 2184.
https://aquila.usm.edu/dissertations/2184