000277532 001__ 277532
000277532 005__ 20250323001000.0
000277532 0247_ $$2doi$$a10.1038/s41420-025-02374-3
000277532 0247_ $$2pmid$$apmid:40075110
000277532 0247_ $$2altmetric$$aaltmetric:175139137
000277532 037__ $$aDZNE-2025-00428
000277532 041__ $$aEnglish
000277532 082__ $$a610
000277532 1001_ $$00000-0002-8380-8990$$aRaas, Quentin$$b0
000277532 245__ $$aTBK1 is involved in programmed cell death and ALS-related pathways in novel zebrafish models.
000277532 260__ $$aLondon$$bNature Publishing Group$$c2025
000277532 3367_ $$2DRIVER$$aarticle
000277532 3367_ $$2DataCite$$aOutput Types/Journal article
000277532 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1742380609_6428
000277532 3367_ $$2BibTeX$$aARTICLE
000277532 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000277532 3367_ $$00$$2EndNote$$aJournal Article
000277532 520__ $$aPathogenic mutations within the TBK1 gene leading to haploinsufficiency are causative of amyotrophic lateral sclerosis (ALS). This gene is linked to autophagy and inflammation, two cellular mechanisms reported to be dysregulated in ALS patients, although its functional role in the pathogenesis could involve other players. We targeted the TBK1 ortholog in zebrafish, an optimal vertebrate model for investigating genetic defects in neurological disorders. We generated zebrafish models with invalidating tbk1 mutations using CRISPR-Cas9 or tbk1 knockdown models using antisense morpholino oligonucleotide (AMO). The early motor phenotype of zebrafish injected with tbk1 AMO beginning at 2 days post fertilization (dpf) is associated with the degeneration of motor neurons. In parallel, CRISPR-induced tbk1 mutants exhibit impaired motor function beginning at 5 dpf and increased lethality beginning at 9 dpf. A metabolomic analysis showed an association between tbk1 loss and severe dysregulation of nicotinamide metabolism, and incubation with nicotinamide riboside rescued the motor behavior of tbk1 mutant zebrafish. Furthermore, a proteomic analysis revealed increased levels of inflammatory markers and dysregulation of programmed cell death pathways. Necroptosis appeared to be strongly activated in TBK1 fish, and larvae treated with the necroptosis inhibitor necrosulfonamide exhibited improved survival. Finally, a combined analysis of mutant zebrafish and TBK1-mutant human motor neurons revealed dysregulation of the KEGG pathway 'ALS', with disrupted nuclear-cytoplasmic transport and increased expression of STAT1. These findings point toward a major role for necroptosis in the degenerative features and premature lethality observed in tbk1 mutant zebrafish. Overall, the novel tbk1-deficient zebrafish models offer a great opportunity to better understand the cascade of events leading from the loss of tbk1 expression to the onset of motor deficits, with involvement of a metabolic defect and increased cell death, and for the development of novel therapeutic avenues for ALS and related neuromuscular diseases.
000277532 536__ $$0G:(DE-HGF)POF4-353$$a353 - Clinical and Health Care Research (POF4-353)$$cPOF4-353$$fPOF IV$$x0
000277532 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
000277532 7001_ $$aHaouy, Gregoire$$b1
000277532 7001_ $$00000-0002-6246-0833$$ade Calbiac, Hortense$$b2
000277532 7001_ $$aPasho, Elena$$b3
000277532 7001_ $$aMarian, Anca$$b4
000277532 7001_ $$00000-0002-4832-6793$$aGuerrera, Ida Chiara$$b5
000277532 7001_ $$aRosello, Marion$$b6
000277532 7001_ $$0P:(DE-2719)9001560$$aOeckl, Patrick$$b7$$udzne
000277532 7001_ $$00000-0001-8551-2846$$aDel Bene, Filippo$$b8
000277532 7001_ $$0P:(DE-2719)9001873$$aCatanese, Alberto$$b9$$udzne
000277532 7001_ $$aCiura, Sorana$$b10
000277532 7001_ $$aKabashi, Edor$$b11
000277532 773__ $$0PERI:(DE-600)2842546-7$$a10.1038/s41420-025-02374-3$$gVol. 11, no. 1, p. 98$$n1$$p98$$tCell death discovery$$v11$$x2058-7716$$y2025
000277532 8564_ $$uhttps://pub.dzne.de/record/277532/files/DZNE-2025-00428%20SUP.zip
000277532 8564_ $$uhttps://pub.dzne.de/record/277532/files/DZNE-2025-00428.pdf$$yOpenAccess
000277532 8564_ $$uhttps://pub.dzne.de/record/277532/files/DZNE-2025-00428.pdf?subformat=pdfa$$xpdfa$$yOpenAccess
000277532 909CO $$ooai:pub.dzne.de:277532$$pdnbdelivery$$pdriver$$pVDB$$popen_access$$popenaire
000277532 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)9001560$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b7$$kDZNE
000277532 9101_ $$0I:(DE-HGF)0$$6P:(DE-2719)9001873$$aExternal Institute$$b9$$kExtern
000277532 9131_ $$0G:(DE-HGF)POF4-353$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vClinical and Health Care Research$$x0
000277532 9141_ $$y2025
000277532 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2024-12-21
000277532 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2024-12-21
000277532 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2024-12-21
000277532 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2024-12-21
000277532 915__ $$0LIC:(DE-HGF)CCBY4$$2HGFVOC$$aCreative Commons Attribution CC BY 4.0
000277532 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2024-12-21
000277532 915__ $$0StatID:(DE-HGF)0501$$2StatID$$aDBCoverage$$bDOAJ Seal$$d2024-04-10T15:36:08Z
000277532 915__ $$0StatID:(DE-HGF)0500$$2StatID$$aDBCoverage$$bDOAJ$$d2024-04-10T15:36:08Z
000277532 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2024-12-21
000277532 915__ $$0StatID:(DE-HGF)0700$$2StatID$$aFees$$d2024-12-21
000277532 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2024-12-21
000277532 915__ $$0StatID:(DE-HGF)0510$$2StatID$$aOpenAccess
000277532 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bDOAJ : Anonymous peer review$$d2024-04-10T15:36:08Z
000277532 915__ $$0StatID:(DE-HGF)0561$$2StatID$$aArticle Processing Charges$$d2024-12-21
000277532 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2024-12-21
000277532 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2024-12-21
000277532 9201_ $$0I:(DE-2719)5000073$$kAG Öckl$$lTranslational Mass Spectrometry and Biomarker Research$$x0
000277532 980__ $$ajournal
000277532 980__ $$aVDB
000277532 980__ $$aUNRESTRICTED
000277532 980__ $$aI:(DE-2719)5000073
000277532 9801_ $$aFullTexts