ArticleThe Journal of experimental medicine2024
A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.
Article in The Journal of experimental medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 17 citations in OpenAlex.
- TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.EMBO reports · 2026Article
- Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.The Journal of clinical investigation · 2026Review
- Annexin A11 and TDP-43: core players in neurodegeneration.Acta neuropathologica · 2026Review
- TBK1 activity regulates the directionality of axonal transport of signalling endosomes.Life science alliance · 2026Article
- Review
- Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.Frontiers in neuroscience · 2026Review
- From knowledge landscapes to network mechanisms: charting regulated cell death pathways in ALS.Frontiers in aging neuroscience · 2026Article
- Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.Cell reports · 2025Article
- Optineurin Shapes Basal and LPS-Induced Transcriptomes in BV2 Microglia.International journal of molecular sciences · 2025Article
- Exploring TANK-Binding Kinase 1 in Amyotrophic Lateral Sclerosis: From Structural Mechanisms to Machine Learning-Guided Therapeutics.Life (Basel, Switzerland) · 2025Review
- Comparing loss of individual fragile X proteins suggests strong links to cellular senescence and aging.Cellular and molecular life sciences : CMLS · 2025Article
- Inborn errors of canonical autophagy in neurodegenerative diseases.Human molecular genetics · 2025Review
- ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice.Nature communications · 2025Article
- Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.Molecular neurobiology · 2025Review
- TBK1 is involved in programmed cell death and ALS-related pathways in novel zebrafish models.Cell death discovery · 2025Article
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD.Nature structural & molecular biology · 2024Article
Corrections and comments
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Authors and funding
31 authors at 7 institutions in 2 countries.
Funding
Abstract
Heterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.
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Registered trials
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.