TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons.
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.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
Benjamin M
BM
Schwenk
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Hannelore
H
Hartmann
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Institute for Advanced Study Technische Universität München, München, Germany.
Alperen
A
Serdaroglu
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
Martin H
MH
Schludi
Max Planck Institute of Biochemistry, Martinsried, Germany.
Daniel
D
Hornburg
Max Planck Institute of Biochemistry, Martinsried, Germany.
Felix
F
Meissner
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Denise
D
Orozco
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Alessio
A
Colombo
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Sabina
S
Tahirovic
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Meike
M
Michaelsen
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Franziska
F
Schreiber
LIFE & BRAIN GmbH, Bonn, Germany.
Simone
S
Haupt
Institute of Reconstructive Neurobiology University of Bonn, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Michael
M
Peitz
Institute of Reconstructive Neurobiology University of Bonn, Bonn, Germany.
Oliver
O
Brüstle
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.|Department of Neurology, Friedrich-Baur-Institute LMU Munich, Munich, Germany.
Clemens
C
Küpper
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.|Department of Neurology, Friedrich-Baur-Institute LMU Munich, Munich, Germany.
Thomas
T
Klopstock
Department of Neurology, University of Ulm, Ulm, Germany.
Markus
M
Otto
Department of Neurology, University of Ulm, Ulm, Germany.
Albert C
AC
Ludolph
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany.|Department of Psychiatry and Psychotherapy, LMU Munich, Munich, Germany.
Thomas
T
Arzberger
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Institute for Advanced Study Technische Universität München, München, Germany.|Institut für Allgemeine Pathologie Klinikum rechts der Isar der Technischen Universität München, München, Germany.
Peer-Hendrik
PH
Kuhn
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany dieter.edbauer@dzne.de.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.|Institute for Metabolic Biochemistry LMU Munich, Munich, Germany.
Dieter
0000-0002-7186-4653
D
Edbauer
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction
C503812:CHMP2B protein, human; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C000598624:TARDBP protein, human; C587689:ERBB4 protein, human; C496348:FGFR1 protein, human; D066247:Receptor, ErbB-4; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C490304:VPS4B protein, human
ALS; ErbB4; FTLD; TDP‐43; recycling endosomes