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

doi:10.1016/j.celrep.2020.02.060

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

Chair of Developmental Genetics

Research output: Contribution to journal › Article › peer-review

54 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 language	English
Pages (from-to)	3506-3519.e6
Journal	Cell Reports
Volume	30
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2020.02.060
State	Published - 10 Mar 2020

Keywords

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

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10.1016/j.celrep.2020.02.060

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Lüningschrör, P., Werner, G., Stroobants, S., Kakuta, S., Dombert, B., Sinske, D., Wanner, R., Lüllmann-Rauch, R., Wefers, B., Wurst, W., D'Hooge, R., Uchiyama, Y., Sendtner, M., Haass, C., Saftig, P., Knöll, B., Capell, A., & Damme, M. (2020). The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons. Cell Reports, 30(10), 3506-3519.e6. https://doi.org/10.1016/j.celrep.2020.02.060

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title = "The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons",

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.",

keywords = "FTLD, TMEM106B, axon, axon initial segment, frontotemporal lobar degeneration, lysosome, motoneurons, retrograde",

author = "Patrick L{\"u}ningschr{\"o}r and Georg Werner and Stijn Stroobants and Soichiro Kakuta and Benjamin Dombert and Daniela Sinske and Renate Wanner and Renate L{\"u}llmann-Rauch and Benedikt Wefers and Wolfgang Wurst and Rudi D'Hooge and Yasuo Uchiyama and Michael Sendtner and Christian Haass and Paul Saftig and Bernd Kn{\"o}ll and Anja Capell and Markus Damme",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = mar,

day = "10",

doi = "10.1016/j.celrep.2020.02.060",

language = "English",

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Lüningschrör, P, Werner, G, Stroobants, S, Kakuta, S, Dombert, B, Sinske, D, Wanner, R, Lüllmann-Rauch, R, Wefers, B, Wurst, W, D'Hooge, R, Uchiyama, Y, Sendtner, M, Haass, C, Saftig, P, Knöll, B, Capell, A & Damme, M 2020, 'The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons', Cell Reports, vol. 30, no. 10, pp. 3506-3519.e6. https://doi.org/10.1016/j.celrep.2020.02.060

TY - JOUR

T1 - The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons

AU - Lüningschrör, Patrick

AU - Werner, Georg

AU - Stroobants, Stijn

AU - Kakuta, Soichiro

AU - Dombert, Benjamin

AU - Sinske, Daniela

AU - Wanner, Renate

AU - Lüllmann-Rauch, Renate

AU - Wefers, Benedikt

AU - Wurst, Wolfgang

AU - D'Hooge, Rudi

AU - Uchiyama, Yasuo

AU - Sendtner, Michael

AU - Haass, Christian

AU - Saftig, Paul

AU - Knöll, Bernd

AU - Capell, Anja

AU - Damme, Markus

PY - 2020/3/10

Y1 - 2020/3/10

N2 - 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.

AB - 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.

KW - FTLD

KW - TMEM106B

KW - axon

KW - axon initial segment

KW - frontotemporal lobar degeneration

KW - lysosome

KW - motoneurons

KW - retrograde

UR - http://www.scopus.com/inward/record.url?scp=85080997290&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2020.02.060

DO - 10.1016/j.celrep.2020.02.060

M3 - Article

C2 - 32160553

AN - SCOPUS:85080997290

SN - 2211-1247

VL - 30

SP - 3506-3519.e6

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

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

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Keywords

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