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

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

Authors :
Dhakal S
Wyant CE
George HE
Morgan SE
Rangachari V
Source :
Journal of molecular biology [J Mol Biol] 2021 May 14; Vol. 433 (10), pp. 166953. Date of Electronic Publication: 2021 Mar 24.
Publication Year :
2021

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.<br />Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Published by Elsevier Ltd.)

Details

Language :
English
ISSN :
1089-8638
Volume :
433
Issue :
10
Database :
MEDLINE
Journal :
Journal of molecular biology
Publication Type :
Academic Journal
Accession number :
33771571
Full Text :
https://doi.org/10.1016/j.jmb.2021.166953