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000268729 1001_ $$0P:(DE-2719)9002137$$aBrenner, David$$b0$$udzne
000268729 245__ $$aA TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice.
000268729 260__ $$aNew York, NY$$bRockefeller Univ. Press$$c2024
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000268729 520__ $$aHeterozygous mutations in the TBK1 gene can cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The majority of TBK1-ALS/FTD patients carry deleterious loss-of-expression mutations, and it is still unclear which TBK1 function leads to neurodegeneration. We investigated the impact of the pathogenic TBK1 missense variant p.E696K, which does not abolish protein expression, but leads to a selective loss of TBK1 binding to the autophagy adaptor protein and TBK1 substrate optineurin. Using organelle-specific proteomics, we found that in a knock-in mouse model and human iPSC-derived motor neurons, the p.E696K mutation causes presymptomatic onset of autophagolysosomal dysfunction in neurons precipitating the accumulation of damaged lysosomes. This is followed by a progressive, age-dependent motor neuron disease. Contrary to the phenotype of mice with full Tbk1 knock-out, RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and overt autoinflammation were not detected. Our in vivo results indicate autophagolysosomal dysfunction as a trigger for neurodegeneration and a promising therapeutic target in TBK1-ALS/FTD.
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000268729 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProtein Serine-Threonine Kinases
000268729 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aTBK1 protein, human
000268729 650_7 $$0EC 2.7.1.-$$2NLM Chemicals$$aTbk1 protein, mouse
000268729 650_2 $$2MeSH$$aAnimals
000268729 650_2 $$2MeSH$$aHumans
000268729 650_2 $$2MeSH$$aMice
000268729 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000268729 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000268729 650_2 $$2MeSH$$aFrontotemporal Dementia: metabolism
000268729 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000268729 650_2 $$2MeSH$$aMotor Neurons: pathology
000268729 650_2 $$2MeSH$$aMutation
000268729 650_2 $$2MeSH$$aNeuroinflammatory Diseases
000268729 650_2 $$2MeSH$$aPhosphorylation
000268729 650_2 $$2MeSH$$aProtein Serine-Threonine Kinases: genetics
000268729 650_2 $$2MeSH$$aProtein Serine-Threonine Kinases: metabolism
000268729 7001_ $$0P:(DE-2719)9002569$$aSieverding, Kirsten$$b1
000268729 7001_ $$00009-0003-8416-2276$$aSrinidhi, Jahnavi$$b2
000268729 7001_ $$00000-0002-8523-824X$$aZellner, Susanne$$b3
000268729 7001_ $$0P:(DE-2719)9000380$$aSecker, Christopher$$b4
000268729 7001_ $$00000-0002-4261-5236$$aYilmaz, Rüstem$$b5
000268729 7001_ $$00000-0003-1423-9322$$aDyckow, Julia$$b6
000268729 7001_ $$00009-0000-1597-1510$$aAmr, Shady$$b7
000268729 7001_ $$00009-0009-9223-9310$$aPonomarenko, Anna$$b8
000268729 7001_ $$00009-0002-4266-4449$$aTunaboylu, Esra$$b9
000268729 7001_ $$00009-0004-7079-7120$$aDouahem, Yasmin$$b10
000268729 7001_ $$00009-0005-2001-4121$$aSchlag, Joana S$$b11
000268729 7001_ $$0P:(DE-2719)9001702$$aRodriguez Martinez, Lucia$$b12$$udzne
000268729 7001_ $$0P:(DE-2719)9000614$$aKislinger, Georg$$b13
000268729 7001_ $$0P:(DE-2719)9001883$$aNiemann, Cornelia$$b14$$udzne
000268729 7001_ $$0P:(DE-2719)9002811$$aNalbach, Karsten$$b15$$udzne
000268729 7001_ $$0P:(DE-2719)9001522$$aRuf, Wolfgang P$$b16
000268729 7001_ $$00009-0005-1754-173X$$aUhl, Jonathan$$b17
000268729 7001_ $$00009-0009-9877-7822$$aHollenbeck, Johanna$$b18
000268729 7001_ $$00000-0001-7142-4116$$aSchirmer, Lucas$$b19
000268729 7001_ $$0P:(DE-2719)9001873$$aCatanese, Alberto$$b20$$udzne
000268729 7001_ $$00000-0002-4313-010X$$aLobsiger, Christian S$$b21
000268729 7001_ $$0P:(DE-2719)9001513$$aDanzer, Karin M$$b22
000268729 7001_ $$00000-0003-1483-0286$$aYilmazer-Hanke, Deniz$$b23
000268729 7001_ $$00000-0003-3832-090X$$aMünch, Christian$$b24
000268729 7001_ $$0P:(DE-2719)9002165$$aKoch, Philipp$$b25$$udzne
000268729 7001_ $$0P:(DE-2719)9001054$$aFreischmidt, Axel-Dieter$$b26
000268729 7001_ $$0P:(DE-2719)2812260$$aFetting, Martina$$b27
000268729 7001_ $$00000-0002-9184-7607$$aBehrends, Christian$$b28
000268729 7001_ $$00000-0001-6682-9645$$aParlato, Rosanna$$b29
000268729 7001_ $$0P:(DE-2719)9000455$$aWeishaupt, Jochen H$$b30
000268729 773__ $$0PERI:(DE-600)1477240-1$$a10.1084/jem.20221190$$gVol. 221, no. 5, p. e20221190$$n5$$pe20221190$$tJournal of experimental medicine$$v221$$x0022-1007$$y2024
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