title: The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death.
abstract: A common genetic variation in the transmembrane protein 106B (TMEM106B) gene has been suggested to be a risk factor for frontotemporal lobar degeneration (FTLD) with inclusions of transactive response DNA-binding protein-43 (TDP-43) (FTLD-TDP), the most common pathological subtype in FTLD. Furthermore, previous studies have shown that TMEM106B levels are up-regulated in the brains of FTLD-TDP patients, although the significance of this finding remains unknown. In this study, we show that the overexpression of TMEM106B and its N-terminal fragments induces cell death, enhances oxidative stress-induced cytotoxicity, and causes the cleavage of TDP-43, which represents TDP-43 pathology, using cell-based models. TMEM106B-induced death is mediated by the caspase-dependent mitochondrial cell death pathways and possibly by the lysosomal cell death pathway. These findings suggest that the up-regulation of TMEM106B may increase the risk of FTLD by directly causing neurotoxicity and a pathological phenotype linked to FTLD-TDP.
authors: From the Departments of Pharmacology and.
authors: Hiroaki
authors: H
authors: Suzuki
authors: From the Departments of Pharmacology and sakimatu@tokyo-med.ac.jp.|Dermatological Neuroscience, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
authors: Masaaki
authors: M
authors: Matsuoka
mesh_terms: D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C000598624:TARDBP protein, human; C556915:TMEM106B protein, human; D020169:Caspases
keywords: Frontotemporal lobar degeneration; TAR DNA-binding protein 43 (TDP-43) (TARDBP); Transmembrane protein 106B; amyotrophic lateral sclerosis (ALS) (Lou Gehrig's disease); cell death; lysosome; neurodegenerative disease