ArticleCell reports2025
Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.
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Article in Cell reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 15 papers.
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15citing papers in PubMed
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Who cites it
15 citing papers in PubMed.
- Functional Activity of TDP-43: A Direct Biomarker for ALS.Biosensors · 2026Article
- An ALS-associated mutation in the C-terminal α-helix of TDP-43 uncouples condensate formation and amyloid assembly.Protein science : a publication of the Protein Society · 2026Article
- Liquid-liquid phase separation in cancer: oncogenic roles, therapeutic potential, and epigenetic regulation.Molecular biology reports · 2026Review
- Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.bioRxiv : the preprint server for biology · 2026Article
- Calcineurin depletion coincides with phosphorylated TDP-43 deposition in a mouse model of ALS/FTLD-TDP.Acta neuropathologica communications · 2026Article
- Axonal transport impairment as an upstream mechanism in amyotrophic lateral sclerosis pathogenesis.Frontiers in neuroscience · 2026Article
- Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis.Brain communications · 2026Review
- Assay for In-Vitro Arginine Methylation of RNA Binding Proteins Followed by RNA Binding.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Excitotoxicity in amyotrophic lateral sclerosis: a key pathogenic mechanism.Brain communications · 2026Review
- PRMT1 in Health and Disease: Emerging Perspectives From Molecular Mechanisms to Therapeutic Strategies.MedComm · 2025Review
- Review
- Molecular simulations of enzymatic phosphorylation of disordered proteins and their condensates.Nature communications · 2025Article
- Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration.Molecular neurodegeneration · 2025Review
- Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.Cells · 2025Review
- TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm.Communications biology · 2025Article
Corrections and comments
- Erratum issued
Authors and funding
32 authors.
Mari AikioAstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA; Neumora Therapeutics, Watertown, MA 02472, USA.
Hana M OdehDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Heike J WobstNeuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA.
Bo Lim LeeDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Úna ChanCenter for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
Jocelyn C MaunaDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; University of Pittsburgh Brain Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Korrie L MackNeumora Therapeutics, Watertown, MA 02472, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Bradley ClassNeuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA.
Thomas A OllerheadAstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA.
Alice F FordDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Edward M BarbieriDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ryan R CupoDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Lauren E DrakeDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Joshua L SmalleyAstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA.
Yuan-Ta LinNeumora Therapeutics, Watertown, MA 02472, USA.
Stephanie LamCenter for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
Reuben ThomasGladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA.
Nicholas CastelloCenter for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
Ashmita BaralCenter for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
Jenna N BeyerDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mohd A NajarDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
John DunlopNeumora Therapeutics, Watertown, MA 02472, USA; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA.
Aaron D GitlerDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ashkan JavaherianCenter for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
Julia A KayeCenter for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA; Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA 94158, USA.
George M BurslemDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Dean G BrownHit Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA.
Christopher J DonnellyDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; University of Pittsburgh Brain Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Steven FinkbeinerCenter for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA; Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA 94158, USA; Deparments of Neurology and Physiology, Neuroscience Graduate Program and Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Stephen J MossAstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA.
Nicholas J BrandonAstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University, Boston, MA 02111, USA; Neumora Therapeutics, Watertown, MA 02472, USA; Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA 02451, USA.
James ShorterDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jshorter@pennmedicine.upenn.edu.
Funding
Training in Alzheimer’s and Age-Related Neurodegenerative DiseasesT32AG000255 · NIA · UNIVERSITY OF PENNSYLVANIA · PI ALICE S CHEN-PLOTKIN, VIRGINIA M LEE · 1997 to 2026
$12.5MIdentification of TDP-43 Modifiers Through Single-Cell Transcriptional and Epigenomic Dissection of ALS and FTLD-MNDR01NS127187 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BELZIL, VERONIQUE, DONNELLY, CHRISTOPHER JAMES · 2021 to 2025
$9.1MSTRUCTURAL BIOLOGY TRAINING PROGRAMT32GM008275 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI WAND, A. JOSHUA · 1988 to 2018
$6.0MDefining the mechanistic basis of a prion disaggregaseR01GM099836 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI SHORTER, JAMES · 2013 to 2024
$3.9MEditing Acetylation and Protein HomeostasisR35GM142505 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI George Burslem · 2021 to 2026
$2.7MImage Tools for Computational Cellular Barcoding and Automated AnnotationR01LM013617 · NLM · J. DAVID GLADSTONE INSTITUTES · PI FINKBEINER, STEVEN M · 2022 to 2025
$1.6MProgramming human protein disaggregases against FTDR21AG065854 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SHORTER, JAMES · 2020 to 2020
$446kSynthetic Reconstruction of Human Chaperone Networks in Yeast Models of NeurodegenerationK99AG075242 · NIA · UNIVERSITY OF PENNSYLVANIA · PI BARBIERI, EDWARD MATTHEW · 2023 to 2024
$231kProgramming Human Chaperone Systems Against Neurodegenerative DiseaseF32NS108598 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI BARBIERI, EDWARD MATTHEW · 2019 to 2021
$193kEngineering mitochondrial protein disaggregases for neurodegenerative diseaseF31AG060672 · NIA · UNIVERSITY OF PENNSYLVANIA · PI CUPO, RYAN R · 2018 to 2020
$122kMechanisms and modifiers of hnRNPA1 and hnRNPA2 misfolding and toxicityF31NS087676 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI FORD, ALICE FLYNN · 2014 to 2016
$77kNIA NIH HHS F31 AG060672NIA NIH HHS K99 AG075242NIA NIH HHS R21 AG065854NIA NIH HHS T32 AG000255NIGMS NIH HHS R01 GM099836NIGMS NIH HHS R35 GM142505NIGMS NIH HHS T32 GM008275NINDS NIH HHS F31 NS087676NINDS NIH HHS F32 NS108598NINDS NIH HHS R01 NS127187NLM NIH HHS R01 LM013617
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we show that p38α MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38α MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38α MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.
Indexed as
ArginineDNA-Binding ProteinsMitogen-Activated Protein Kinase 14Protein-Arginine N-MethyltransferasesRepressor ProteinsTDP-43 ProteinopathiesAmyotrophic Lateral SclerosisHEK293 CellsHumansMethylationMotor NeuronsPhosphorylationArginineDNA-Binding ProteinsMitogen-Activated Protein Kinase 14PRMT1 protein, humanProtein-Arginine N-MethyltransferasesRepressor ProteinsTARDBP protein, humanALSarginine methylationCP: Molecular biologyCP: Neurosciencep38αphosphorylationPRMT1TDP-43
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