ArticleCell2020
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.
2 registry-linked trialsOpen access · hybridAbstract read
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Article in Cell, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 605 papers, 1 of them a synthesis that pooled it.
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605citing papers in PubMed, 1 pooled it
41.2field-weighted citation impact, top 1% of its field
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
NCT06782958 phase1enrolling by invitationnot on this mapstarted 2024, after this paper: background citation
A Phase I Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetic Characteristics of FHND1002 Granules After Single and Multiple Doses in Healthy Adult Volunteers
NCT07138014 phase2not yet recruitingnot on this mapstarted 2025, after this paper: background citation
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II Study to Evaluate the Efficacy and Safety of FHND1002 Granules in Patients With Amyotrophic Lateral Sclerosis (ALS)
Who cites it
605 citing papers in PubMed, 1 synthesis or guideline pooled it, 940 citations in OpenAlex.
- What can we learn on ALS pathophysiology from iPSC-derived motor neurons harbouring TARBDP mutations: a systematic review.Translational neurodegeneration · 2026Pooled it
- Mitochondria-targeted MXene-based nanozymes promote mitophagy and inhibit mtDNA-triggered cGAS/STING inflammation in osteoarthritis.Bioactive materials · 2026Article
- Modeling human neurodegeneration with iPSCs: opportunities, limitations, and the challenge of aging.The Journal of clinical investigation · 2026Review
- TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.EMBO reports · 2026Article
- From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).Experimental and therapeutic medicine · 2026Review
- Ultrasound-Responsive Piezoelectric Fibrous Membrane Promotes Neurological Recovery After TBI by Modulating Microglial Polarization via Restoring Mitochondrial Dynamic Homeostasis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Basophil Extracellular Traps in Immunity and Disease.Cancers · 2026Review
- UA-30 ameliorates motor deficits through RalA-mediated mitophagy in ALS mice.The Journal of clinical investigation · 2026Article
- Clonal CD8 T cells link peripheral and intrathecal immunity in ALS4 progression: a multiomics reference for ALS.Research square · 2026Article
- The Role of cGAS-STING-Driven PANoptosis in Neurodegenerative Diseases and Therapeutic Prospects.Cells · 2026Review
- Mitochondrial Transplantation Suppresses mtDNA-cGAS/STING-Mediated Innate Immunity by Enhancing PINK1/Parkin-Dependent Mitophagy to Attenuate Keloid Fibrosis.Antioxidants (Basel, Switzerland) · 2026Article
- cGAS-STING pathway modulation: A new hope for neural regeneration.Neural regeneration research · 2026Article
- Astragaloside IV Mitigates Subarachnoid Hemorrhage-Induced Brain Injury via Regulating Microglial Polarization and Neuroinflammation Mediated by cGAS/STING Pathway.Chinese journal of integrative medicine · 2026Article
- Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 2026Review
- Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.Neural regeneration research · 2026Article
- Individual and Combined Cytotoxic Effects of Zearalenone and Zearalenone-14-Glucoside in Porcine Intestinal Epithelial Cells.Veterinary sciences · 2026Article
- Acute viral infection accelerates neurodegeneration in a mouse model of ALS.Nature communications · 2026Article
- Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis.Translational neurodegeneration · 2026Review
- The cGAS-STING pathway in inflammaging and neuroinflammation.Science China. Life sciences · 2026Review
- Protease-Mediated TAR DNA-Binding Protein 43 (TDP-43) Pathogenesis: From Molecular Mechanisms to Therapeutic Opportunities.ACS pharmacology & translational science · 2026Review
545 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 6 institutions in 3 countries.
Chien-Hsiung YuInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Sophia DavidsonInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Cassandra R HarapasInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
James B HiltonDepartment of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia.
Michael J MlodzianoskiCentre for Dynamic Imaging, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Pawat LaohamonthonkulInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Cynthia LouisInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Ronnie Ren Jie LowPersonalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Jonas MoeckingInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Institute of Structural Biology, University of Bonn, 53127 Bonn, Germany.
Dominic De NardoInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia.
Katherine R BalkaInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia.
Dale J CallejaInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Fiona MoghaddasInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Immunology and Allergy, The Royal Melbourne Hospital, Parkville, VIC 3052, Australia.
Erya NiInfection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Catriona A McLeanAnatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
Andre L SamsonInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Shiraz TyebjiInfection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Christopher J TonkinInfection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Christopher R ByeFlorey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia.
Bradley J TurnerFlorey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia.
Genevieve PepinCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia.
Michael P GantierCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia.
Kelly L RogersCentre for Dynamic Imaging, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Kate McArthurDepartment of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia.
Peter J CrouchDepartment of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia.
Seth L MastersInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Immunology Laboratory, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou, Guangdong 510623, China. Electronic address: masters@wehi.edu.au.
The University of Melbourne · AUHudson Institute of Medical Research · AUMonash University · AUThe Alfred Hospital · AUThe Royal Melbourne Hospital · AUUniversity of Bonn · DE
Funding
Howard Hughes Medical InstituteWellcome Trust 208694/Z/17/Z
Abstract
Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.
Indexed as
AlarminsAmyotrophic Lateral SclerosisAnimalsCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseCytoplasmDisease Models, AnimalDisease ProgressionDNA-Binding ProteinsDNA, MitochondrialHEK293 CellsHumansInduced Pluripotent Stem CellsInflammationInterferon Type IMembrane ProteinsMiceAlarminscGAS protein, humancGAS protein, mouseCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseDNA-Binding ProteinsDNA, MitochondrialInterferon Type IMembrane ProteinsMitochondrial Permeability Transition PoreNF-kappa BNucleotidyltransferasesPhosphotransferases (Alcohol Group Acceptor)Protein SubunitsSTING1 protein, humanSting1 protein, mouseSTING ProteinTARDBP protein, humanTardbp protein, mouseALScGAMPcGASIFNmitochondriamPTPneurodegenerationNF-κBSTINGTDP-43
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Read underepoch 390
Registered trials
NCT06782958ClinicalTrials.gov
NCT07138014ClinicalTrials.gov
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.