title: TMEM106B, a frontotemporal lobar dementia (FTLD) modifier, associates with FTD-3-linked CHMP2B, a complex of ESCRT-III.
abstract: BACKGROUND
  Transmembrane protein 106B (TMEM106B) has been identified as a risk factor for frontotemporal lobar degeneration, which is the second most common form of progressive dementia in people under 65 years of age. Mutations in charged multivesicular body protein 2B (CHMP2B), which is involved in endosomal protein trafficking, have been found in chromosome 3-linked frontotemporal dementia. Despite the number of studies on both CHMP2B and TMEM106B in the endolysosomal pathway, little is known about the relationship between CHMP2B and TMEM106B in the endosomal/autophagy pathway.
  
  
  RESULTS
  This study found that endogenous TMEM106B was partially sequestered in CHMP2B-positive structures, suggesting its possible involvement in endosomal sorting complexes required for transport (ESCRT)-associated pathways. The role of single nucleotide polymorphisms of TMEM106B (T185, S185, or S134N) in the ESCRT-associated pathways were characterized. The T185 and S185 variants were more localized to Rab5-/Rab7-positive endosomes compared with S134N, while all of the variants were more localized to Rab7-positive endosomes compared to Rab5-positive endosomes. T185 was more associated with CHMP2B compared to S185. Autophagic flux was slightly reduced in the T185-expressing cells compared to the control or S185-expressing cells. Moreover, T185 slightly enhanced the accumulation of EGFR, impairments in autophagic flux, and neurotoxicity that were caused by CHMP2B(Intron5) compared to S185-expressing cells.
  
  
  CONCLUSIONS
  These findings suggest that the T185 variant functions as a risk factor in neurodegeneration with endolysosomal defects. This study provides a better understanding of pathogenic functions of TMEM106B, which is a risk factor for the progression of neurodegenerative diseases that are associated with endosomal defects in the aged brain.
authors.affiliation: Department of Biotechnology and Biological Sciences, Hannam University, 1646 Yuseongdaero, Yu-seong-gu, Daejeon, 305-811, South Korea. mhjun8872@gmail.com.
authors.forename: Mi-Hee
authors.initials: MH
authors.lastname: Jun
authors.affiliation: Department of Biotechnology and Biological Sciences, Hannam University, 1646 Yuseongdaero, Yu-seong-gu, Daejeon, 305-811, South Korea. kangshinmu@nate.com.
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Biotechnology and Biological Sciences, Hannam University, 1646 Yuseongdaero, Yu-seong-gu, Daejeon, 305-811, South Korea. alskgogo77@gmail.com.
authors.forename: Yu-Kyung
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Applied Biology, College of Ecological Environment, Kyungpook National University, 386, Gajang-dong, Sang-Ju, South Korea. jangdj@knu.ac.kr.
authors.forename: Deok-Jin
authors.initials: DJ
authors.lastname: Jang
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Gwanak-gu, Seoul, 08826, South Korea. kaang@snu.ac.kr.
authors.forename: Bong-Kiun
authors.initials: BK
authors.lastname: Kaang
authors.affiliation: Department of Biotechnology and Biological Sciences, Hannam University, 1646 Yuseongdaero, Yu-seong-gu, Daejeon, 305-811, South Korea. leeja@hnu.kr.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Lee
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011992:Endosomes / Q000737:chemistry / Q000502:physiology*; D005091:Exons / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007438:Introns / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps; D021381:Protein Transport / Q000502:physiology*; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000032:analysis; D020696:rab5 GTP-Binding Proteins / Q000032:analysis; D000090802:rab7 GTP-Binding Proteins
chemical_list: C503812:CHMP2B protein, human; C525139:CHMP2B protein, mouse; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C556915:TMEM106B protein, human; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; C427755:RAB5C protein, human; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins