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Open Access

The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes

Benjamin M. Schwenk, Christina M. Lang, Sebastian Hogl, Sabina Tahirovic, Denise Orozco, Kristin Rentzsch, Stefan F. Lichtenthaler, Casper C. Hoogenraad, Anja Capell, Christian Haass, Dieter Edbauer

Author Affiliations

  1. Benjamin M. Schwenk1,
  2. Christina M. Lang2,
  3. Sebastian Hogl1,
  4. Sabina Tahirovic1,
  5. Denise Orozco1,
  6. Kristin Rentzsch1,
  7. Stefan F. Lichtenthaler1,3,4,
  8. Casper C. Hoogenraad5,
  9. Anja Capell2,
  10. Christian Haass1,2,4 and
  11. Dieter Edbauer*,1,2,4
  1. 1German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
  2. 2Biochemistry, Adolf Butenandt Institute Ludwig‐Maximilians University, Munich, Germany
  3. 3Neuroproteomics, Klinikum rechts der Isar Technische Universität München, Munich, Germany
  4. 4Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
  5. 5Cell Biology Faculty of Science, Utrecht University, Utrecht, The Netherlands
  1. *Corresponding author. Tel: +49 (0)89 / 2180 ‐ 75453; Fax: +49 (0) 89 / 2180 ‐ 75415; E‐mail: dieter.edbauer{at}dzne.de
  1. BMS and DE conceived the experiments. BMS performed and analyzed most experiments in neurons and rat brain. CML performed the analysis in heterologous cells. SH and SFL performed mass spectrometry analyses. DO and ST analyzed the axonal phenotype. KR and DE generated reagents. CCH, AC, CH and DE supervised research. BMS and DE wrote the manuscript with input from all coauthors.

Abstract

TMEM106B is a major risk factor for frontotemporal lobar degeneration with TDP‐43 pathology. TMEM106B localizes to lysosomes, but its function remains unclear. We show that TMEM106B knockdown in primary neurons affects lysosomal trafficking and blunts dendritic arborization. We identify microtubule‐associated protein 6 (MAP6) as novel interacting protein for TMEM106B. MAP6 over‐expression inhibits dendritic branching similar to TMEM106B knockdown. MAP6 knockdown fully rescues the dendritic phenotype of TMEM106B knockdown, supporting a functional interaction between TMEM106B and MAP6. Live imaging reveals that TMEM106B knockdown and MAP6 overexpression strongly increase retrograde transport of lysosomes in dendrites. Downregulation of MAP6 in TMEM106B knockdown neurons restores the balance of anterograde and retrograde lysosomal transport and thereby prevents loss of dendrites. To strengthen the link, we enhanced anterograde lysosomal transport by expressing dominant‐negative Rab7‐interacting lysosomal protein (RILP), which also rescues the dendrite loss in TMEM106B knockdown neurons. Thus, TMEM106B/MAP6 interaction is crucial for controlling dendritic trafficking of lysosomes, presumably by acting as a molecular brake for retrograde transport. Lysosomal misrouting may promote neurodegeneration in patients with TMEM106B risk variants.

Synopsis

Embedded Image

GWAS studies identified TMEM106B a major risk factor for frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology. This study combines loss‐off‐function experiments, live‐imaging and proteomics to elucidate the function of the lysosomal protein TMEM106B in neurons.

  • Co‐immunoprecipitation experiments and mass‐spectrometry show that TMEM106B interacts with microtubule‐associated protein 6 (MAP6).

  • TMEM106B knockdown promotes retrograde transport of dendritic lysosomes and dendrite loss, which is phenocopied by MAP6 overexpression.

  • MAP6 knockdown rebalances dendritic trafficking of lysosomes and fully rescues the dendritic phenotype of TMEM106B knockdown.

  • Promoting anterograde lysosomal transport using dominant negative Rab7‐interacting lysosomal protein (RILP) rescues dendrite loss in TMEM106B knockdown neurons.

  • TMEM106B/MAP6 interaction controls dendritic branching, presumably by providing a molecular brake for retrograde dendritic trafficking of lysosomes.

Footnotes

  • The authors declare that they have no conflict of interest.

  • Received May 31, 2013.
  • Revision received October 7, 2013.
  • Accepted October 27, 2013.

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