The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons
Summary: 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472030228X |
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doaj-6a9f42b14fca4fb8a5526634d9334b2c |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons Cell Reports |
| author_facet |
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 |
| author_sort |
Patrick Lüningschrör |
| title |
The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons |
| title_short |
The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons |
| title_full |
The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons |
| title_fullStr |
The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons |
| title_full_unstemmed |
The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons |
| title_sort |
ftld risk factor tmem106b regulates the transport of lysosomes at the axon initial segment of motoneurons |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2020-03-01 |
| description |
Summary: 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. : Genetic variants in the TMEM106B gene, coding for a lysosomal transmembrane protein, are linked to various neurodegenerative diseases. The function of TMEM106B remains enigmatic. Lüningschrör et al. analyze Tmem106b-knockout mice and find drastically enlarged LAMP1-positive vacuoles in proximal axons of selected motoneuron nuclei. Vacuolization is caused by impaired axonal transport. Keywords: TMEM106B, frontotemporal lobar degeneration, lysosome, retrograde, axon, axon initial segment, motoneurons, FTLD |
| url |
http://www.sciencedirect.com/science/article/pii/S221112472030228X |
| work_keys_str_mv |
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doaj-6a9f42b14fca4fb8a5526634d9334b2c2020-11-25T01:21:30ZengElsevierCell Reports2211-12472020-03-01301035063519.e6The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of MotoneuronsPatrick Lüningschrör0Georg Werner1Stijn Stroobants2Soichiro Kakuta3Benjamin Dombert4Daniela Sinske5Renate Wanner6Renate Lüllmann-Rauch7Benedikt Wefers8Wolfgang Wurst9Rudi D’Hooge10Yasuo Uchiyama11Michael Sendtner12Christian Haass13Paul Saftig14Bernd Knöll15Anja Capell16Markus Damme17Institute of Clinical Neurobiology, University Hospital Wuerzburg, University of Wuerzburg, 97078 Wuerzburg, GermanyChair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, GermanyLaboratory of Biological Psychology, KU Leuven, 3000 Leuven, BelgiumDepartment of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, JapanInstitute of Clinical Neurobiology, University Hospital Wuerzburg, University of Wuerzburg, 97078 Wuerzburg, GermanyInstitute of Physiological Chemistry, Ulm University, 89081 Ulm, GermanyInstitute of Physiological Chemistry, Ulm University, 89081 Ulm, GermanyInstitute for Anatomy, Kiel University, 24098 Kiel, GermanyGerman Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, GermanyGerman 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, GermanyLaboratory of Biological Psychology, KU Leuven, 3000 Leuven, BelgiumDepartment of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, JapanInstitute of Clinical Neurobiology, University Hospital Wuerzburg, University of Wuerzburg, 97078 Wuerzburg, GermanyChair 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, GermanyInstitute of Biochemistry, Kiel University, 24098 Kiel, GermanyInstitute of Physiological Chemistry, Ulm University, 89081 Ulm, GermanyChair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, GermanyInstitute of Biochemistry, Kiel University, 24098 Kiel, Germany; Corresponding authorSummary: 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. : Genetic variants in the TMEM106B gene, coding for a lysosomal transmembrane protein, are linked to various neurodegenerative diseases. The function of TMEM106B remains enigmatic. Lüningschrör et al. analyze Tmem106b-knockout mice and find drastically enlarged LAMP1-positive vacuoles in proximal axons of selected motoneuron nuclei. Vacuolization is caused by impaired axonal transport. Keywords: TMEM106B, frontotemporal lobar degeneration, lysosome, retrograde, axon, axon initial segment, motoneurons, FTLDhttp://www.sciencedirect.com/science/article/pii/S221112472030228X |