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EMBO J. 2016 Nov 2;35(21):2350-2370. Epub 2016 Sep 12.

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

Author information

1
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
2
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
3
Institute for Advanced Study Technische Universität München, München, Germany.
4
Max Planck Institute of Biochemistry, Martinsried, Germany.
5
LIFE & BRAIN GmbH, Bonn, Germany.
6
Institute of Reconstructive Neurobiology University of Bonn, Bonn, Germany.
7
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
8
Department of Neurology, Friedrich-Baur-Institute LMU Munich, Munich, Germany.
9
Department of Neurology, University of Ulm, Ulm, Germany.
10
Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany.
11
Department of Psychiatry and Psychotherapy, LMU Munich, Munich, Germany.
12
Institut für Allgemeine Pathologie Klinikum rechts der Isar der Technischen Universität München, München, Germany.
13
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany dieter.edbauer@dzne.de.
14
Institute for Metabolic Biochemistry LMU Munich, Munich, Germany.

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 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.

KEYWORDS:

ALS; ErbB4; FTLD; TDP‐43; recycling endosomes

PMID:
27621269
PMCID:
PMC5090220
DOI:
10.15252/embj.201694221
[Indexed for MEDLINE]
Free PMC Article

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