While deleterious mutations are responsible for the vast majority of TBK1-linked ALS/FTD cases, the ALS/FTD causing missense mutation p.E696K leads to a selective loss of TBK1/optineurin binding. Knock-in of this specific missense mutation causes progressive autophagolysosomal dysfunction and an ALS/FTD-like phenotype in mice, while, as opposed to TBK1 deletion, RIPK/TNF-α-dependent necroptosis or overt inflammation are absent. Our results highlight the role of autophagolysosomal dysfunction as a therapeutic target in TBK1-ALS/FTD.
Export PNG
Views: 28
Created: 9th Jul 2024 at 12:57
This item has not yet been tagged.
None
Version History
Version 1 (earliest) Created 9th Jul 2024 at 12:57 by Rainer Malik
No revision comments
Related items
Projects: SyNergy - published datasets
Institutions: DZNE
Projects: SyNergy - published datasets
Institutions: Klinikum der Universität München
Public web page: Not specified
Organisms: Mus musculus, Rattus norvegicus, Homo sapiens, Macaca mulatta, Sus scrofa
Submitter: Rainer Malik
Studies: ACSL3/GABARAPL2 interactor, ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte D..., AMPK/Lysosomal Damage/Galectins, An optimized quantitative proteomics method establishes the cell type-re..., Autophagosome content profiling, Autophagy cargo/CD4+ T cell proliferation, BAG3-mediated autophagy, Basic Fibroblast Growth Factor 2-Induced Proteome Changes Endorse Lewy B..., Beneficial Effect of ACI-24 Vaccination on Aβ Plaque Pathology and Micro..., C9orf72/UBR5/Quality control, CCNF/ALS, CNN2/Lysosome damage, COP9 signalosome/Ischemic stroke, Cell-type-specific profiling of brain mitochondria reveals functional an..., Deciphering sources of PET signals in the tumor microenvironment of glio..., Endothelial Aging, Experimental evidence for temporal uncoupling of brain Aβ deposition and..., Fibrillar Aβ triggers microglial proteome alterations and dysfunction in..., Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in..., Lysosomal targeting of TAPL, NDP52 interactome, Neuronal differentiation of LUHMES cells is accompanied by substantial c..., NrCAM is a marker for substrate-selective activation of ADAM10 in Alzhei..., Pro-inflammatory activation following demyelination is required for myel..., Protein content of autophagic vesicles, Proteolysis enhanced proximity proteomics, Proteomic and lipidomic profiling of demyelinating lesions identifies fa..., Proteomic profiling in cerebral amyloid angiopathy reveals an overlap wi..., Proteomics of inflammasome activation for rapid immune responses, Proteomics of mouse brain endothelium uncovers dysregulation of vesicula..., Reactivated endogenous retroviruses promote protein aggregate spreading, Signal peptide peptidase-like 2c impairs vesicular transport and cleaves..., Signatures of glial activity can be detected in the CSF proteome, Spatial proteomics in three-dimensional intact specimens, Spatial proteomics reveals secretory pathway disturbances caused by neur..., TBK1/ALS, TECPR2/secretory pathway, Targeting the TCA cycle can ameliorate widespread axonal energy deficien..., The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 si..., The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulat..., The intramembrane protease SPPL2c promotes male germ cell development by..., The pseudoprotease iRhom1 controls ectodomain shedding of membrane prote..., The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor com..., UBE2QL1/Lysosome damage, UBQLN2/ALS
Assays: Affinity purification coupled with mass spectrometry proteomics, Affinity purification coupled with mass spectrometry proteomics, Affinity purification coupled with mass spectrometry proteomics, Affinity purification coupled with mass spectrometry proteomics, Affinity purification coupled with mass spectrometry proteomics, Affinity purification coupled with mass spectrometry proteomics, Affinity purification coupled with mass spectrometry proteomics, Bottom-up proteomics, Gel-based experiment, Proteomics analysis of brain endothelial cells, Proteomics of Inflammasome, SWATH MS, Shotgun Proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics, Shotgun proteomics
Snapshots: Snapshot 1
While deleterious mutations are responsible for the vast majority of TBK1-linked ALS/FTD cases, the ALS/FTD causing missense mutation p.E696K leads to a selective loss of TBK1/optineurin binding. Knock-in of this specific missense mutation causes progressive autophagolysosomal dysfunction and an ALS/FTD-like phenotype in mice, while, as opposed to TBK1 deletion, RIPK/TNF-α-dependent necroptosis or overt inflammation are absent. Our results highlight the role of autophagolysosomal dysfunction as ...
Snapshots: No snapshots
Samples were lysed with lysis buffer (2% SDS, 50mM Tris-HCl pH 8.5, 10mM TCEP, 40mM chloroacetamide and protease inhibitor cocktail tablet [EDTA-free, Roche]). Samples were incubated for 5 minutes at 95°C before sonication with Sonic Vibra Cell at 1s ON/ 1s OFF pulse for 30s at a maximal amplitude of 30% to shear genomic DNA. After sonication, samples were incubated for 10min at 95°C. Proteins were precipitated using 3 volumes of ice-cold methanol, 1 volume Chloroform and 2.5 volumes ddH2O. After ...
Submitter: Rainer Malik
Assay type: Experimental Assay Type
Technology type: Technology Type
Investigation: Proteomics
Study: TBK1/ALS
Organisms: Mus musculus
SOPs: No SOPs
Data files: TBK1 p.E696K mutation causes autophagolysosomal...
Snapshots: No snapshots
Abstract (Expand)
Authors: D. Brenner, K. Sieverding, J. Srinidhi, S. Zellner, C. Secker, R. Yilmaz, J. Dyckow, S. Amr, A. Ponomarenko, E. Tunaboylu, Y. Douahem, J. S. Schlag, L. Rodriguez Martinez, G. Kislinger, C. Niemann, K. Nalbach, W. P. Ruf, J. Uhl, J. Hollenbeck, L. Schirmer, A. Catanese, C. S. Lobsiger, K. M. Danzer, D. Yilmazer-Hanke, C. Munch, P. Koch, A. Freischmidt, M. Fetting, C. Behrends, R. Parlato, J. H. Weishaupt
Date Published: 6th May 2024
Publication Type: Journal
PubMed ID: 38517332
Citation: J Exp Med. 2024 May 6;221(5):e20221190. doi: 10.1084/jem.20221190. Epub 2024 Mar 22.