Prion-Like C-Terminal Domain of TDP-43 and α-Synuclein Interact Synergistically to Generate Neurotoxic Hybrid Fibrils

Authors

Shailendra Dhakal, University of Southern MississippiFollow
Courtney E. Wyant, University of Southern Mississippi
Hannah E. George, University of Southern MississippiFollow
Sarah E. Morgan, University of Southern MississippiFollow
Vijayaraghavan Rangachari, University of Southern MississippiFollow

Document Type

Article

Publication Date

5-14-2021

School

Polymer Science and Engineering

Abstract

Aberrant aggregation and amyloid formation of tar DNA binding protein (TDP-43) and α-synuclein (αS) underlie frontotemporal dementia (FTD) and Parkinson’s disease (PD), respectively. Amyloid inclusions of TDP-43 and αS are also commonly co-observed in amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB) and Alzheimer disease (AD). Emerging evidence from cellular and animal models show colocalization of the TDP-43 and αS aggregates, raising the possibility of direct interactions and co-aggregation between the two proteins. In this report, we set out to answer this question by investigating the interactions between αS and prion-like pathogenic C-terminal domain of TDP-43 (TDP-43 PrLD). PrLD is an aggregation-prone fragment generated both by alternative splicing as well as aberrant proteolytic cleavage of full length TDP-43. Our results indicate that two proteins interact in a synergistic manner to augment each other’s aggregation towards hybrid fibrils. While monomers, oligomers and sonicated fibrils of αS seed TDP-43 PrLD monomers, TDP-43 PrLD fibrils failed to seed αS monomers indicating selectivity in interactions. Furthermore, αS modulates liquid droplets formed by TDP-43 PrLD and RNA to promote insoluble amyloid aggregates. Importantly, the cross-seeded hybrid aggregates show greater cytotoxicity as compared to the individual homotypic aggregates suggesting that the interactions between the two proteins have a discernable impact on cellular functions. Together, these results bring forth insights into TDP-43 PrLD – αS interactions that could help explain clinical and pathological presentations in patients with co-morbidities involving the two proteins.

Comments

© 2021. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/.

Publication Title

Journal of Molecular Biology

Volume

433

Issue

10

Recommended Citation

Dhakal, S., Wyant, C., George, H., Morgan, S., Rangachari, V. (2021). Prion-Like C-Terminal Domain of TDP-43 and α-Synuclein Interact Synergistically to Generate Neurotoxic Hybrid Fibrils. Journal of Molecular Biology, 433(10).
Available at: https://aquila.usm.edu/fac_pubs/18849