ArticleNeurobiology of aging2018
ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function.
Registry-linked trialOpen access · hybridAbstract read
In one paragraph
Article in Neurobiology of aging, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01459302 (Family Studies in Neuromuscular Disorders), which is not on this map. Cited by 51 papers.
0numbers the graph read from it
0cells of the map it votes in
51citing papers in PubMed
7.8field-weighted citation impact, top 2% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Family Studies in Neuromuscular Disorders
Who cites it
51 citing papers in PubMed, 82 citations in OpenAlex.
- TBK1 overexpression reduces neuronal loss in the P497S UBQLN2 mouse model of ALS/FTD.Neurobiology of disease · 2026Article
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Review
- Recurrent severe viral infection in a child with inherited complete TBK1 deficiency.Journal of human immunity · 2026Article
- Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.Frontiers in neuroscience · 2026Review
- Boosting Brain Clean-Up: Can Targeting UPS Genes Offer Neuroprotection?Molecular neurobiology · 2025Review
- Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.Cell reports · 2025Article
- Glutamic Acid at Position 168 Is a Constitutive Activator of Tank Binding Kinase 1 Catalytic Function.Neuromolecular medicine · 2025Article
- Exploring TANK-Binding Kinase 1 in Amyotrophic Lateral Sclerosis: From Structural Mechanisms to Machine Learning-Guided Therapeutics.Life (Basel, Switzerland) · 2025Review
- Inborn errors of canonical autophagy in neurodegenerative diseases.Human molecular genetics · 2025Review
- Targeting mitophagy in neurodegenerative diseases.Nature reviews. Drug discovery · 2025Review
- Interferon Regulatory Factors as a Potential Therapeutic Target for Neuroinflammation: A Focus on Alzheimer's Disease.International journal of molecular sciences · 2025Review
- TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism.Journal of the Chinese Medical Association : JCMA · 2024Article
- Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations.Alzheimer's research & therapy · 2024Article
- The Inflammatory Puzzle: Piecing together the Links between Neuroinflammation and Amyotrophic Lateral Sclerosis.Aging and disease · 2024Review
- A Next-Generation Sequencing Study in a Cohort of Sicilian Patients with Parkinson's Disease.Biomedicines · 2023Article
- Functional Characterization of a Familial ALS-Associated MissenseInternational journal of molecular sciences · 2023Article
- Vascular and Nonvascular Mechanisms of Cognitive Impairment and Dementia.Clinics in geriatric medicine · 2023Review
- Frustration analysis of TBK1 missense mutations reported in ALS/FTD and cancer patients.3 Biotech · 2022Article
- Autophagy Dysfunction in ALS: from Transport to Protein Degradation.Journal of molecular neuroscience : MN · 2022Review
Corrections and comments
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Authors and funding
33 authors at 13 institutions in 6 countries.
Martina de MajoUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Simon D ToppUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Bradley N SmithUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Agnes L NishimuraUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Han-Jou ChenUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Athina Soragia GkaziUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Jack MillerUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Chun Hao WongUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Caroline VanceUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Frank BaasDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Anneloor L M A Ten AsbroekDepartment of Genome analysis, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands.
Kevin P KennaDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA.
Nicola TicozziDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Centre, Università degli Studi di Milano, Milan, Italy.
Alberto Garcia RedondoUnidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, SERMAS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), Madrid, Spain.
Jesús Esteban-PérezUnidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, SERMAS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), Madrid, Spain.
Cinzia TilocaDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Centre, Università degli Studi di Milano, Milan, Italy.
Federico VerdeDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Centre, Università degli Studi di Milano, Milan, Italy.
Stefano DugaDepartment of Biomedical Sciences, Humanitas University, Rozzano-Milan, Italy; Humanitas Clinical and Research Center, Rozzano-Milan, Italy.
Karen E MorrisonUniversity of Southampton, Southampton General Hospital, UK.
Pamela J ShawSheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Janine KirbySheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Martin R TurnerNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Kevin TalbotNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Orla HardimanAcademic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.
Jonathan D GlassDepartment of Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
Jacqueline de BellerocheNeurogenetics Group, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London, UK.
Cinzia GelleraUnit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
Antonia RattiDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Centre, Università degli Studi di Milano, Milan, Italy.
Ammar Al-ChalabiUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Robert H BrownDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA.
Vincenzo SilaniDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Centre, Università degli Studi di Milano, Milan, Italy.
John E LandersDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA.
Christopher E ShawUnited Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address: chris.shaw@kcl.ac.uk.
King's College London · GBUniversity of Massachusetts Chan Medical School · USUniversity of Milan · ITResearch Institute Hospital 12 de Octubre · ESEmory University · USHammersmith Hospital · GBHumanitas University · ITLeiden University Medical Center · NLSouthampton General Hospital · GBTrinity College Dublin · IEUniversity of Amsterdam · NLUniversity of Oxford · GBUniversity of Sheffield · GB
Funding
Identification of genes causative for familial ALS gene using exome sequencingR01NS073873 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI LANDERS, JOHN E · 2011 to 2019
$4.6MMedical Research Council G0500289Medical Research Council G0600974Medical Research Council MC_G1000733Medical Research Council MC_PC_17115Medical Research Council MR/K01014X/1Medical Research Council MR/L021803/1Medical Research Council MR/L501529/1Medical Research Council MR/R024804/1Motor Neurone Disease Association ALCHALABI-DOBSON/APR14/829-791Motor Neurone Disease Association SHAW/APR15/933-794Motor Neurone Disease Association SHAW/APR15/970-797Motor Neurone Disease Association SHAW/NOV14/985-797Motor Neurone Disease Association SMITH/APR16/847-791Motor Neurone Disease Association SMITH/OCT16/888-792Motor Neurone Disease Association TURNER/JAN13/944-795Motor Neurone Disease Association TURNER/OCT18/989-797MRF_ MRF-060-0003-RG-SMITHNINDS NIH HHS R01 NS073873Wellcome Trust
Abstract
Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the p.R357X and p.G217R both abolish the ability of TBK1 to phosphorylate 2 of its kinase targets, IRF3 and optineurin, and to undergo phosphorylation. They both inhibit binding to optineurin and the p.G217R, within the TBK1 kinase domain, reduces homodimerization, essential for TBK1 activation and function. Finally, we show that the proportion of TBK1 that is active (phosphorylated) is reduced in 5 lymphoblastoid cell lines derived from patients harboring heterozygous missense or in-frame deletion TBK1 mutations. We conclude that missense mutations in functional domains of TBK1 impair the binding and phosphorylation of its normal targets, implicating a common loss of function mechanism, analogous to truncation mutations.
Indexed as
Amyotrophic Lateral SclerosisCell Cycle ProteinsCodon, NonsenseExonsFemaleGenetic Association StudiesHumansInterferon Regulatory Factor-3MaleMembrane Transport ProteinsMutation, MissensePhosphorylationProtein BindingProtein Serine-Threonine KinasesProtein Structure, TertiaryTranscription Factor TFIIIACell Cycle ProteinsCodon, NonsenseInterferon Regulatory Factor-3IRF3 protein, humanMembrane Transport ProteinsOPTN protein, humanProtein Serine-Threonine KinasesTBK1 protein, humanTranscription Factor TFIIIAALSFamilial ALSFTDTBK1WES
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Read underepoch 390
Registered trials
NCT01459302ClinicalTrials.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.