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000270416 1001_ $$0P:(DE-2719)9000587$$aHu, Yiying$$b0$$eFirst author$$udzne
000270416 245__ $$aMis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits.
000270416 260__ $$aLondon$$bBiomed Central$$c2024
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000270416 520__ $$aThe key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing.CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis.CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish's embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction.The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression.
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000270416 650_7 $$2Other$$aALS
000270416 650_7 $$2Other$$aAnimal model
000270416 650_7 $$2Other$$aHypothalamus
000270416 650_7 $$2Other$$aMetabolic dysfunction
000270416 650_7 $$2Other$$aNeurodegeneration
000270416 650_7 $$2Other$$aTDP-43
000270416 650_7 $$2Other$$aZebrafish
000270416 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000270416 650_7 $$2NLM Chemicals$$aZebrafish Proteins
000270416 650_7 $$2NLM Chemicals$$aTardbp protein, zebrafish
000270416 650_2 $$2MeSH$$aAnimals
000270416 650_2 $$2MeSH$$aZebrafish
000270416 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000270416 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000270416 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000270416 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000270416 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000270416 650_2 $$2MeSH$$aDisease Models, Animal
000270416 650_2 $$2MeSH$$aMotor Neurons: metabolism
000270416 650_2 $$2MeSH$$aMotor Neurons: pathology
000270416 650_2 $$2MeSH$$aZebrafish Proteins: metabolism
000270416 650_2 $$2MeSH$$aZebrafish Proteins: genetics
000270416 650_2 $$2MeSH$$aAnimals, Genetically Modified
000270416 650_2 $$2MeSH$$aNeuromuscular Junction: metabolism
000270416 650_2 $$2MeSH$$aNeuromuscular Junction: pathology
000270416 7001_ $$0P:(DE-2719)2009882$$aHruscha, Alexander$$b1$$udzne
000270416 7001_ $$aPan, Chenchen$$b2
000270416 7001_ $$0P:(DE-2719)2812260$$aSchifferer, Martina$$b3$$udzne
000270416 7001_ $$aSchmidt, Michael K$$b4
000270416 7001_ $$aNuscher, Brigitte$$b5
000270416 7001_ $$aGiera, Martin$$b6
000270416 7001_ $$aKostidis, Sarantos$$b7
000270416 7001_ $$0P:(DE-2719)2812704$$aBurhan, Özge$$b8$$udzne
000270416 7001_ $$0P:(DE-2719)9000319$$avan Bebber, Frauke$$b9$$udzne
000270416 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b10$$udzne
000270416 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b11$$udzne
000270416 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b12$$udzne
000270416 7001_ $$0P:(DE-2719)2241638$$aSchmid, Bettina$$b13$$eLast author
000270416 773__ $$0PERI:(DE-600)2244557-2$$a10.1186/s13024-024-00735-7$$gVol. 19, no. 1, p. 50$$n1$$p50$$tMolecular neurodegeneration$$v19$$x1750-1326$$y2024
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