ArticleHuman molecular genetics2013
The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers, 2 of them syntheses that pooled it.
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Who cites it
113 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.Brain : a journal of neurology · 2017Pooled it
- TDP-43 as a possible biomarker for frontotemporal lobar degeneration: a systematic review of existing antibodies.Acta neuropathologica communications · 2015Pooled it
- Review
- TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.BMC medicine · 2026Review
- Stability and Dynamics of the N‑Terminal Domain of TDP-43 and the Effect of Point Mutations.ACS omega · 2026Article
- Understanding liquid-liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation.Genome biology · 2026Review
- Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis.Brain communications · 2026Review
- Deciphering the role of APOE in cerebral amyloid angiopathy: from genetic insights to therapeutic horizons.Annals of medicine · 2025Review
- Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.Cells · 2025Review
- The Regulation of TDP-43 Structure and Phase Transitions: A Review.The protein journal · 2025Review
- Detection of an Intermediate in the Unfolding Process of the N-Terminal Domain of TDP-43.ACS omega · 2025Article
- TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.Cell reports · 2025Article
- Review
- Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS.Nature communications · 2024Article
- Article
- Aberrant protein aggregation in amyotrophic lateral sclerosis.Journal of neurology · 2024Review
- Biophysical characterization of the phase separation of TDP-43 devoid of the C-terminal domain.Cellular & molecular biology letters · 2024Article
- Heterotypic interactions can drive selective co-condensation of prion-like low-complexity domains of FET proteins and mammalian SWI/SNF complex.Nature communications · 2024Article
- Recombinant Full-Length TDP-43 Oligomers Retain Their Ability to Bind RNAs, Are Not Toxic, and Do Not Seed TDP-43 Aggregation in Vitro.ACS chemical neuroscience · 2024Article
53 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
TAR DNA-binding protein-43 (TDP-43) is the principal component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and the most common pathological subtype of frontotemporal dementia-frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP). To date, the C-terminus of TDP-43, which is aggregation-prone and contains almost all ALS-associated mutations, has garnered much attention while the functions of the N-terminus of TDP-43 remain largely unknown. To bridge this gap in our knowledge, we utilized novel cell culture and computer-assisted models to evaluate which region(s) of TDP-43 regulate its folding, self-interaction, biological activity and aggregation. We determined that the extreme N-terminus of TDP-43, specifically the first 10 residues, regulates folding of TDP-43 monomers necessary for proper homodimerization and TDP-43-regulated splicing. Despite such beneficial functions, we discovered an interesting dichotomy: full-length TDP-43 aggregation, which is believed to be a pathogenic process, also requires the extreme N-terminus of TDP-43. As such, we provide new insight into the structural basis for TDP-43 function and aggregation, and we suggest that stabilization of TDP-43 homodimers, the physiologically active form of TDP-43, may be a promising therapeutic strategy for ALS and FTLD-TDP.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.