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

• Benjamin M Schwenk ^[1] ; Hannelore Hartmann ^[1] ; Alperen Serdaroglu ^[1] ; Martin H Schludi ^[1] ; Daniel Hornburg ^[2] ; Felix Meissner ^[2] ; Denise Orozco ^[1] ; Alessio Colombo ^[1] ; Sabina Tahirovic ^[1] ; Meike Michaelsen ^[1] ; Franziska Schreiber ^[1] ; Simone Haupt ^[5] ; Michael Peitz ^[3] ; Oliver Brüstle ^[3] ; Clemens Küpper ^[6] ; Thomas Klopstock ^[1] ; Markus Otto ^[4] ; Albert C Ludolph ^[4] ; Thomas Arzberger ^[1] ; Peer‐Hendrik Kuhn ^[1] ; Dieter Edbauer ^[1]
  1. [1] German Center for Neurodegenerative Diseases

     German Center for Neurodegenerative Diseases

     Kreisfreie Stadt Bonn, Alemania

     
  2. [2] Max Planck Institute of Biochemistry

     Max Planck Institute of Biochemistry

     Kreisfreie Stadt München, Alemania

     
  3. [3] University of Bonn

     University of Bonn

     Kreisfreie Stadt Bonn, Alemania

     
  4. [4] University of Ulm

     University of Ulm

     Stadtkreis Ulm, Alemania

     
  5. [5] 5 LIFE & BRAIN GmbH Bonn Germany
  6. [6] 2 Munich Cluster of Systems Neurology (SyNergy) Munich Germany; 8 Department of Neurology Friedrich‐Baur‐Institute LMU Munich Munich Germany

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 35, Nº. 21, 2016, págs. 2350-2370
• Idioma: inglés
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  • 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.