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TMEM106B, a frontotemporal lobar dementia (FTLD) modifier, associates with FTD-3-linked CHMP2B, a complex of

Mi-Hee Jun1, Jeong-Ho Han2, Yu-Kyung Lee3

  • 1Department of Biotechnology and Biological Sciences, Hannam University, 1646 Yuseongdaero, Yu-seong-gu, Daejeon, 305-811, South Korea. mhjun8872@gmail.com.

Molecular Brain
|December 15, 2015
PubMed
Abstract

Insights

Transmembrane protein 106B (TMEM106B) variants influence endosomal trafficking and autophagy, impacting neurodegeneration risk. The T185 variant exacerbates CHMP2B-associated neurotoxicity, highlighting its role in endolysosomal defects.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Transmembrane protein 106B (TMEM106B) is a risk factor for frontotemporal lobar degeneration, a common dementia.
  • Mutations in charged multivesicular body protein 2B (CHMP2B) are linked to frontotemporal dementia.
  • The relationship between TMEM106B and CHMP2B in endosomal/autophagy pathways is poorly understood.

Purpose of the Study:

  • To investigate the relationship between TMEM106B and CHMP2B in the endosomal/autophagy pathway.
  • To characterize the role of TMEM106B single nucleotide polymorphisms (SNPs) in endosomal sorting complexes required for transport (ESCRT)-associated pathways.

Main Methods:

  • Immunofluorescence microscopy to assess co-localization of TMEM106B variants with endosomal markers (Rab5, Rab7) and CHMP2B.
  • Analysis of autophagic flux in cells expressing different TMEM106B variants.
  • Assessment of EGFR accumulation and neurotoxicity in cells expressing TMEM106B variants and CHMP2B(Intron5).

Main Results:

  • Endogenous TMEM106B partially co-localized with CHMP2B-positive structures.
  • TMEM106B variants T185 and S185 localized more to Rab7-positive endosomes than S134N.
  • The T185 variant showed greater association with CHMP2B, reduced autophagic flux, and enhanced CHMP2B(Intron5)-induced EGFR accumulation, autophagic impairment, and neurotoxicity compared to S185.

Conclusions:

  • The T185 variant of TMEM106B functions as a risk factor in neurodegeneration associated with endolysosomal defects.
  • These findings enhance understanding of TMEM106B's pathogenic roles in age-related neurodegenerative diseases with endosomal dysfunction.

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