Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B

Mol Cell Neurosci. 2014 Jul;61:226-40. doi: 10.1016/j.mcn.2014.07.006. Epub 2014 Jul 24.

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.

Keywords: Fronto-temporal dementia; Lysosome; Neurodegeneration; Progranulin; TDP-43; TFEB.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cells, Cultured
  • Chlorocebus aethiops
  • Embryo, Mammalian
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Luminescent Proteins / metabolism
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Lysosomes / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Protein Transport / genetics*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Stress, Physiological / genetics*
  • Transfection

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Luminescent Proteins
  • Lysosomal-Associated Membrane Protein 1
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • TFEB protein, human
  • TMEM106B protein, human
  • enhanced green fluorescent protein
  • red fluorescent protein
  • Green Fluorescent Proteins