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Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice.

Authors :
Zhou X
Brooks M
Jiang P
Koga S
Zuberi AR
Baker MC
Parsons TM
Castanedes-Casey M
Phillips V
Librero AL
Kurti A
Fryer JD
Bu G
Lutz C
Dickson DW
Rademakers R
Source :
EMBO reports [EMBO Rep] 2020 Oct 05; Vol. 21 (10), pp. e50197. Date of Electronic Publication: 2020 Aug 05.
Publication Year :
2020

Abstract

Progranulin (PGRN) and transmembrane protein 106B (TMEM106B) are important lysosomal proteins implicated in frontotemporal lobar degeneration (FTLD) and other neurodegenerative disorders. Loss-of-function mutations in progranulin (GRN) are a common cause of FTLD, while TMEM106B variants have been shown to act as disease modifiers in FTLD. Overexpression of TMEM106B leads to lysosomal dysfunction, while loss of Tmem106b ameliorates lysosomal and FTLD-related pathologies in young Grn <superscript>-/-</superscript> mice, suggesting that lowering TMEM106B might be an attractive strategy for therapeutic treatment of FTLD-GRN. Here, we generate and characterize older Tmem106b <superscript>-/-</superscript> Grn <superscript>-/-</superscript> double knockout mice, which unexpectedly show severe motor deficits and spinal cord motor neuron and myelin loss, leading to paralysis and premature death at 11-12 months. Compared to Grn <superscript>-/-</superscript> , Tmem106b <superscript>-/-</superscript> Grn <superscript>-/-</superscript> mice have exacerbated FTLD-related pathologies, including microgliosis, astrogliosis, ubiquitin, and phospho-Tdp43 inclusions, as well as worsening of lysosomal and autophagic deficits. Our findings confirm a functional interaction between Tmem106b and Pgrn and underscore the need to rethink whether modulating TMEM106B levels is a viable therapeutic strategy.<br /> (© 2020 The Authors.)

Details

Language :
English
ISSN :
1469-3178
Volume :
21
Issue :
10
Database :
MEDLINE
Journal :
EMBO reports
Publication Type :
Academic Journal
Accession number :
32761777
Full Text :
https://doi.org/10.15252/embr.202050197