ArticleJournal of molecular biology2021
Prion-like C-Terminal Domain of TDP-43 and α-Synuclein Interact Synergistically to Generate Neurotoxic Hybrid Fibrils.
Article in Journal of molecular biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 77 citations in OpenAlex.
- Assessment of Aggregation- and Condensation-Prone Regions of Proteins Involved in Neurodegenerative, Neurological and Mental-State Diseases.Biomolecules · 2026Article
- Review
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- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Roles of RNA-Binding Nuclear Proteins in Alzheimer's Disease Pathophysiology.ACS pharmacology & translational science · 2026Review
- Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy.Molecules (Basel, Switzerland) · 2026Review
- Review
- From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis.International journal of molecular sciences · 2026Review
- Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?Molecular neurodegeneration advances · 2026Review
- Neuropathology of Lewy body dementia: Lewy-related pathology, α-synuclein oligomers, and comorbid pathologies.Molecular neurodegeneration · 2025Review
- Amyloid Cross-Interactions through the Lens of Simulations: The Case of Aβ-IAPP.The journal of physical chemistry. B · 2025Article
- Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein.Molecular neurodegeneration · 2025Review
- Alzheimer's disease and its co-pathologies: Implications for hippocampal degeneration, cognitive decline, and the role of APOE ε4.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Heterotypic Droplet Formation by Pro-Inflammatory S100A9 and Neurodegenerative Disease-Related α-Synuclein.Biomacromolecules · 2025Article
- Chaperone-mediated heterotypic phase separation regulates liquid-to-solid phase transitions of tau into amyloid fibrils.Science advances · 2025Article
- Experimental methods for studying amyloid cross-interactions.Protein science : a publication of the Protein Society · 2025Review
- TDP-43 seeding activity in the olfactory mucosa of patients with amyotrophic lateral sclerosis.Molecular neurodegeneration · 2025Article
- Cross-Interaction with Amyloid-β Drives Pathogenic Structural Transformation within the Amyloidogenic Core Region of TDP-43.ACS chemical neuroscience · 2025Article
- Recent Advances in Co-Condensation and Co-Aggregation of Amyloid Proteins Linked to Neurodegenerative Diseases.Current protein & peptide science · 2025Review
- Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
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.
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