The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons

Patrick Lüningschrör, Georg Werner, Stijn Stroobants, Soichiro Kakuta, Benjamin Dombert, Daniela Sinske, Renate Wanner, Renate Lüllmann-Rauch, Benedikt Wefers, Wolfgang Wurst, Rudi D'Hooge, Yasuo Uchiyama, Michael Sendtner, Christian Haass, Paul Saftig, Bernd Knöll, Anja Capell, Markus Damme

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Genetic variations in TMEM106B, coding for a lysosomal membrane protein, affect frontotemporal lobar degeneration (FTLD) in GRN- (coding for progranulin) and C9orf72-expansion carriers and might play a role in aging. To determine the physiological function of TMEM106B, we generated TMEM106B-deficient mice. These mice develop proximal axonal swellings caused by drastically enlarged LAMP1-positive vacuoles, increased retrograde axonal transport of lysosomes, and accumulation of lipofuscin and autophagosomes. Giant vacuoles specifically accumulate at the distal end and within the axon initial segment, but not in peripheral nerves or at axon terminals, resulting in an impaired facial-nerve-dependent motor performance. These data implicate TMEM106B in mediating the axonal transport of LAMP1-positive organelles in motoneurons and axonal sorting at the initial segment. Our data provide mechanistic insight into how TMEM106B affects lysosomal proteolysis and degradative capacity in neurons.

Original languageEnglish
Pages (from-to)3506-3519.e6
JournalCell Reports
Volume30
Issue number10
DOIs
StatePublished - 10 Mar 2020

Keywords

  • FTLD
  • TMEM106B
  • axon
  • axon initial segment
  • frontotemporal lobar degeneration
  • lysosome
  • motoneurons
  • retrograde

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