TY  - JOUR
AU  - Schwenk, Benjamin M
AU  - Hartmann, Hannelore
AU  - Serdaroglu, Alperen
AU  - Schludi, Martin H
AU  - Hornburg, Daniel
AU  - Meissner, Felix
AU  - Orozco, Denise
AU  - Colombo, Alessio
AU  - Tahirovic, Sabina
AU  - Michaelsen, Meike
AU  - Schreiber, Franziska
AU  - Haupt, Simone
AU  - Peitz, Michael
AU  - Brüstle, Oliver
AU  - Küpper, Clemens
AU  - Klopstock, Thomas
AU  - Otto, Markus
AU  - Ludolph, Albert C
AU  - Arzberger, Thomas
AU  - Kuhn, Peer-Hendrik
AU  - Edbauer, Dieter
TI  - TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons.
JO  - The EMBO journal
VL  - 35
IS  - 21
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-05187
SP  - 2350-2370
PY  - 2016
AB  - 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.
KW  - ATPases Associated with Diverse Cellular Activities
KW  - Adenosine Triphosphatases: genetics
KW  - Adenosine Triphosphatases: metabolism
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Animals
KW  - Cells, Cultured
KW  - DNA-Binding Proteins: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - Endosomal Sorting Complexes Required for Transport: genetics
KW  - Endosomal Sorting Complexes Required for Transport: metabolism
KW  - Endosomes: metabolism
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Gene Knockdown Techniques
KW  - Hippocampus: cytology
KW  - Humans
KW  - Neurons: metabolism
KW  - Protein Transport
KW  - Rats
KW  - Receptor, ErbB-4: genetics
KW  - Receptor, ErbB-4: metabolism
KW  - Receptor, Fibroblast Growth Factor, Type 1: metabolism
KW  - Signal Transduction
KW  - CHMP2B protein, human (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - Endosomal Sorting Complexes Required for Transport (NLM Chemicals)
KW  - TDP-43 protein, human (NLM Chemicals)
KW  - ERBB4 protein, human (NLM Chemicals)
KW  - FGFR1 protein, human (NLM Chemicals)
KW  - Receptor, ErbB-4 (NLM Chemicals)
KW  - Receptor, Fibroblast Growth Factor, Type 1 (NLM Chemicals)
KW  - Adenosine Triphosphatases (NLM Chemicals)
KW  - ATPases Associated with Diverse Cellular Activities (NLM Chemicals)
KW  - VPS4B protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27621269
C2  - pmc:PMC5090220
DO  - DOI:10.15252/embj.201694221
UR  - https://pub.dzne.de/record/138865
ER  -