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  TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons

Schwenk, B. M., Hartmann, H., Serdaroglu, A., Schludi, M. H., Hornburg, D., Meissner, F., et al. (2016). TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons. The EMBO Journal, 35(21), 2350-2370. doi:10.15252/embj.201694221.

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2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license
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 Creators:
Schwenk, Benjamin M.1, Author
Hartmann, Hannelore1, Author
Serdaroglu, Alperen1, Author
Schludi, Martin H.1, Author
Hornburg, Daniel2, Author              
Meissner, Felix3, Author              
Orozco, Denise1, Author
Colombo, Alessio1, Author
Tahirovic, Sabina1, Author
Michaelsen, Meike1, Author
Schreiber, Franziska1, Author
Haupt, Simone1, Author
Peitz, Michael1, Author
Bruestle, Oliver1, Author
Kuepper, Clemens1, Author
Klopstock, Thomas1, Author
Otto, Markus1, Author
Ludolph, Albert C.1, Author
Arzberger, Thomas1, Author
Kuhn, Peer-Hendrik1, Author
Edbauer, Dieter1, Author more..
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
3Meissner, Felix / Experimental Systems Immunology, Max Planck Institute of Biochemistry, Max Planck Society, ou_2149678              

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Free keywords: AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; HEPATOCYTE GROWTH-FACTOR; SPINAL MOTOR-NEURONS; HIPPOCAMPAL-NEURONS; CEREBROSPINAL-FLUID; FAMILIAL ALS; RISK-FACTOR; MUTATIONS; DEMENTIABiochemistry & Molecular Biology; Cell Biology; ALS; ErbB4; FTLD; recycling endosomes; TDP-43;
 Abstract: Nuclear 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 2-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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Language(s): eng - English
 Dates: 2016-09-122016-11-02
 Publication Status: Published in print
 Pages: 21
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000387142500008
DOI: 10.15252/embj.201694221
 Degree: -

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Title: The EMBO Journal
Source Genre: Journal
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Publ. Info: Nature Publishing Group
Pages: - Volume / Issue: 35 (21) Sequence Number: - Start / End Page: 2350 - 2370 Identifier: ISSN: 0261-4189
CoNE: https://pure.mpg.de/cone/journals/resource/954925497061_1