title: Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B.
abstract: Fronto-temporal lobar degeneration with TDP-43 (FTLD-TDP) is a fatal neurodegeneration. TMEM106B variants are linked to FTLD-TDP risk, and TMEM106B is lysosomal. Here, we focus on neuronal TMEM106B, and demonstrate co-localization and traffic with lysosomal LAMP-1. pH-sensitive reporters demonstrate that the TMEM106B C-terminus is lumenal. The TMEM106B N-terminus interacts with endosomal adaptors and other TMEM106 proteins. TMEM106B knockdown reduces neuronal lysosomal number and diameter by STED microscopy, and overexpression enlarges LAMP-positive structures. Reduction of TMEM106B increases axonally transported lysosomes, while TMEM106B elevation inhibits transport and yields large lysosomes in the soma. TMEM106B overexpression alters lysosomal stress signaling, causing a translocation of the mTOR-sensitive transcription factor, TFEB, to neuronal nuclei. TMEM106B loss-of-function delays TFEB translocation after Torin-1-induced stress. Enlarged TMEM106B-overexpressing lysosomes maintain organelle integrity longer after lysosomal photodamage than do control lysosomes, while small TMEM106B-knockdown lysosomes are more sensitive to illumination. Thus, neuronal TMEM106B plays a central role in regulating lysosomal size, motility and responsiveness to stress, highlighting the possible role of lysosomal biology in FTLD-TDP.
authors: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Massimiliano
authors: M
authors: Stagi
authors: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Zoe A
authors: ZA
authors: Klein
authors: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Travis J
authors: TJ
authors: Gould
authors: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors: Joerg
authors: J
authors: Bewersdorf
authors: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: stephen.strittmatter@yale.edu.
authors: Stephen M
authors: SM
authors: Strittmatter
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D014162:Transfection; D000097573:Red Fluorescent Protein
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D052118:Lysosomal-Associated Membrane Protein 1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000097573:Red Fluorescent Protein; C079240:Mtap2 protein, mouse; C064972:TFEB protein, human; C556915:TMEM106B protein, human; C485184:enhanced green fluorescent protein
keywords: Fronto-temporal dementia; Lysosome; Neurodegeneration; Progranulin; TDP-43; TFEB