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The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death

Hiroaki Suzuki1, Masaaki Matsuoka2,3

  • 1From the Departments of Pharmacology and.

The Journal of Biological Chemistry
|August 27, 2016
PubMed

Insights

Increased transmembrane protein 106B (TMEM106B) may raise frontotemporal lobar degeneration (FTLD) risk. Overexpressing TMEM106B causes cell death and TDP-43 pathology, suggesting a direct neurotoxic mechanism in FTLD-TDP.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Transmembrane protein 106B (TMEM106B) genetic variations are linked to frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP).
  • Elevated TMEM106B levels are observed in FTLD-TDP patient brains, but their functional significance is unclear.

Purpose of the Study:

  • To investigate the role of TMEM106B overexpression in cellular toxicity and TDP-43 pathology.
  • To elucidate the cell death pathways involved in TMEM106B-induced neurotoxicity.

Main Methods:

  • Utilized cell-based models to study the effects of TMEM106B and its fragments.
  • Assessed cell death, oxidative stress, and TDP-43 cleavage.
  • Investigated involvement of caspase-dependent mitochondrial and lysosomal cell death pathways.

Main Results:

  • Overexpression of TMEM106B and its N-terminal fragments induced significant cell death.
  • TMEM106B enhanced cytotoxicity under oxidative stress conditions.
  • Cleavage of TDP-43 was observed, indicating the induction of TDP-43 pathology.

Conclusions:

  • Up-regulation of TMEM106B may contribute to FTLD risk by directly causing neurotoxicity.
  • TMEM106B-induced cell death involves caspase-dependent mitochondrial pathways and potentially lysosomal pathways.
  • These findings link TMEM106B to the pathological phenotype of FTLD-TDP.
Keywords:
Frontotemporal lobar degenerationTAR DNA-binding protein 43 (TDP-43) (TARDBP)Transmembrane protein 106Bamyotrophic lateral sclerosis (ALS) (Lou Gehrig's disease)cell deathlysosomeneurodegenerative disease

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