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000138865 1001_ $$0P:(DE-2719)2551184$$aSchwenk, Benjamin M$$b0$$eFirst author$$udzne
000138865 245__ $$aTDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons.
000138865 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2016
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000138865 520__ $$aNuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased β2-transferrin levels in patient CSF Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase reporter assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed the broad reduction in surface expression of key receptors upon TDP-43 knockdown, including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays the surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43-induced neurodegeneration by blocking trophic signaling.
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000138865 542__ $$2Crossref$$i2016-09-12$$uhttp://creativecommons.org/licenses/by-nc-nd/4.0/
000138865 542__ $$2Crossref$$i2016-09-12$$uhttp://doi.wiley.com/10.1002/tdm_license_1.1
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000138865 650_7 $$2NLM Chemicals$$aCHMP2B protein, human
000138865 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000138865 650_7 $$2NLM Chemicals$$aEndosomal Sorting Complexes Required for Transport
000138865 650_7 $$2NLM Chemicals$$aTDP-43 protein, human
000138865 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aERBB4 protein, human
000138865 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aFGFR1 protein, human
000138865 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aReceptor, ErbB-4
000138865 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aReceptor, Fibroblast Growth Factor, Type 1
000138865 650_7 $$0EC 3.6.1.-$$2NLM Chemicals$$aAdenosine Triphosphatases
000138865 650_7 $$0EC 3.6.4.-$$2NLM Chemicals$$aATPases Associated with Diverse Cellular Activities
000138865 650_7 $$0EC 3.6.4.6$$2NLM Chemicals$$aVPS4B protein, human
000138865 650_2 $$2MeSH$$aATPases Associated with Diverse Cellular Activities
000138865 650_2 $$2MeSH$$aAdenosine Triphosphatases: genetics
000138865 650_2 $$2MeSH$$aAdenosine Triphosphatases: metabolism
000138865 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000138865 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000138865 650_2 $$2MeSH$$aAnimals
000138865 650_2 $$2MeSH$$aCells, Cultured
000138865 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000138865 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000138865 650_2 $$2MeSH$$aEndosomal Sorting Complexes Required for Transport: genetics
000138865 650_2 $$2MeSH$$aEndosomal Sorting Complexes Required for Transport: metabolism
000138865 650_2 $$2MeSH$$aEndosomes: metabolism
000138865 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: genetics
000138865 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: metabolism
000138865 650_2 $$2MeSH$$aGene Knockdown Techniques
000138865 650_2 $$2MeSH$$aHippocampus: cytology
000138865 650_2 $$2MeSH$$aHumans
000138865 650_2 $$2MeSH$$aNeurons: metabolism
000138865 650_2 $$2MeSH$$aProtein Transport
000138865 650_2 $$2MeSH$$aRats
000138865 650_2 $$2MeSH$$aReceptor, ErbB-4: genetics
000138865 650_2 $$2MeSH$$aReceptor, ErbB-4: metabolism
000138865 650_2 $$2MeSH$$aReceptor, Fibroblast Growth Factor, Type 1: metabolism
000138865 650_2 $$2MeSH$$aSignal Transduction
000138865 7001_ $$0P:(DE-2719)2811080$$aHartmann, Hannelore$$b1$$udzne
000138865 7001_ $$0P:(DE-2719)2813862$$aSerdaroglu, Alperen$$b2$$udzne
000138865 7001_ $$0P:(DE-2719)2810746$$aSchludi, Martin H$$b3$$udzne
000138865 7001_ $$aHornburg, Daniel$$b4
000138865 7001_ $$aMeissner, Felix$$b5
000138865 7001_ $$0P:(DE-2719)9000242$$aOrozco, Denise$$b6$$udzne
000138865 7001_ $$0P:(DE-2719)2340744$$aColombo, Alessio$$b7$$udzne
000138865 7001_ $$0P:(DE-2719)2442036$$aTahirovic, Sabina$$b8$$udzne
000138865 7001_ $$0P:(DE-2719)2811691$$aMichaelsen, Meike$$b9$$udzne
000138865 7001_ $$0P:(DE-2719)2811212$$aSchreiber, Franziska$$b10$$udzne
000138865 7001_ $$aHaupt, Simone$$b11
000138865 7001_ $$0P:(DE-2719)9000249$$aPeitz, Michael$$b12$$udzne
000138865 7001_ $$0P:(DE-HGF)0$$aBrüstle, Oliver$$b13
000138865 7001_ $$0P:(DE-HGF)0$$aKüpper, Clemens$$b14
000138865 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b15$$udzne
000138865 7001_ $$aOtto, Markus$$b16
000138865 7001_ $$0P:(DE-HGF)0$$aLudolph, Albert C$$b17
000138865 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b18$$udzne
000138865 7001_ $$0P:(DE-2719)2810327$$aKuhn, Peer-Hendrik$$b19$$udzne
000138865 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b20$$eLast author$$udzne
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000138865 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s00401-015-1460-x$$o10.1007/s00401-015-1460-x
000138865 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1074/jbc.M112.359000$$o10.1074/jbc.M112.359000
000138865 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.15252/embj.201591998$$o10.15252/embj.201591998
000138865 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1091/mbc.11.2.747$$o10.1091/mbc.11.2.747