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Cell Rep. 2020 Mar 10;30(10):3506-3519.e6. 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.

Author information

1
Institute of Clinical Neurobiology, University Hospital Wuerzburg, University of Wuerzburg, 97078 Wuerzburg, Germany.
2
Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
3
Laboratory of Biological Psychology, KU Leuven, 3000 Leuven, Belgium.
4
Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
5
Institute of Physiological Chemistry, Ulm University, 89081 Ulm, Germany.
6
Institute for Anatomy, Kiel University, 24098 Kiel, Germany.
7
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
8
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Technische Universität München-Weihenstephan, 85764 Neuherberg/Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
9
Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
10
Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
11
Institute of Biochemistry, Kiel University, 24098 Kiel, Germany. Electronic address: mdamme@biochem.uni-kiel.de.

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

PMID:
32160553
DOI:
10.1016/j.celrep.2020.02.060
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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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