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

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

Author information

1
Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: stephen.strittmatter@yale.edu.

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

PMID:
25066864
PMCID:
PMC4145808
DOI:
10.1016/j.mcn.2014.07.006
[Indexed for MEDLINE]
Free PMC Article

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