1. The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons
- Author
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Bernd Knöll, Renate Lüllmann-Rauch, Paul Saftig, Christian Haass, Yasuo Uchiyama, Wolfgang Wurst, Renate Wanner, Anja Capell, Rudi D'Hooge, Georg Werner, Stijn Stroobants, Patrick Lüningschrör, Benedikt Wefers, Daniela Sinske, Soichiro Kakuta, Michael Sendtner, Benjamin Dombert, and Markus Damme
- Subjects
0301 basic medicine ,MODIFIER ,Vacuole ,pathology [Facial Nerve] ,VARIANTS ,Axonal Transport ,metabolism [Lysosomes] ,0302 clinical medicine ,innervation [Muscles] ,Risk Factors ,Axon ,lcsh:QH301-705.5 ,genetics [Nerve Tissue Proteins] ,Mice, Knockout ,Motor Neurons ,DEMENTIA ,Muscles ,ultrastructure [Autophagosomes] ,ultrastructure [Axon Initial Segment] ,Frontotemporal lobar degeneration ,metabolism [Autophagosomes] ,Cell biology ,genetics [Membrane Proteins] ,Facial Nerve ,medicine.anatomical_structure ,genetics [Frontotemporal Lobar Degeneration] ,Life Sciences & Biomedicine ,PROTEINS ,Nerve Tissue Proteins ,ultrastructure [Motor Neurons] ,Biology ,General Biochemistry, Genetics and Molecular Biology ,MECHANISMS ,Lipofuscin ,03 medical and health sciences ,pathology [Brain Stem] ,MOTILITY ,Lysosome ,Organelle ,medicine ,Animals ,Genetic Predisposition to Disease ,ddc:610 ,metabolism [Cell Nucleus] ,PROGRANULIN ,deficiency [Membrane Proteins] ,Axon Initial Segment ,Cell Nucleus ,FRONTOTEMPORAL LOBAR DEGENERATION ,Science & Technology ,deficiency [Nerve Tissue Proteins] ,MUTATIONS ,Autophagosomes ,metabolism [Axon Initial Segment] ,Membrane Proteins ,ultrastructure [Lysosomes] ,metabolism [Motor Neurons] ,Cell Biology ,medicine.disease ,Axon initial segment ,Mice, Inbred C57BL ,030104 developmental biology ,nervous system ,lcsh:Biology (General) ,Axoplasmic transport ,Frontotemporal Lobar Degeneration ,Lysosomes ,030217 neurology & neurosurgery ,Brain Stem - Abstract
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
- Published
- 2020
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