ArticleMolecular neurobiology2021
SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution.
Article in Molecular neurobiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 45 citations in OpenAlex.
- TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.BMC medicine · 2026Review
- The Role of Stress Granules in Cardiovascular Diseases.Reviews in cardiovascular medicine · 2026Review
- TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation.Biochemistry and biophysics reports · 2026Review
- Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis.Brain communications · 2026Review
- TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.The FEBS journal · 2026Review
- PIAS1/PIAS4-Mediated SUMOylation of TDP-43 Is Induced by Oxidative Stress.bioRxiv : the preprint server for biology · 2025Article
- Dimer-Specific FokT-seq Reveals DNA-Binding Dimerization and Novel Genomic Targets of TDP-43.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The mechanisms underlying TDP-43-associated neurodegeneration in Alzheimer's disease and related dementias.Molecular psychiatry · 2025Review
- Current Understanding of Protein Aggregation in Neurodegenerative Diseases.International journal of molecular sciences · 2025Review
- Induced proximity to PML protects TDP-43 from aggregation via SUMO-ubiquitin networks.Nature chemical biology · 2025Article
- Critical impact of lysine 136 in TDP-43 phase separation, compartmentalization, and aggregation in living vertebrates.iScience · 2025Article
- Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.Cells · 2025Review
- A stress-dependent TDP-43 SUMOylation program preserves neuronal function.Molecular neurodegeneration · 2025Article
- SUMO2/3 conjugation of TDP-43 protects against aggregation.Science advances · 2025Article
- SUMOylation balance: a key determinant in synapse physiology.Frontiers in physiology · 2025Review
- Decoding TDP-43: the molecular chameleon of neurodegenerative diseases.Acta neuropathologica communications · 2024Review
- Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Prion-like Spreading of Disease in TDP-43 Proteinopathies.Brain sciences · 2024Review
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106-110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.
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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.