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

Xiaolai Zhou, Mieu Brooks, Peizhou Jiang, Shunsuke Koga, Aamir R. Zuberi, Matthew C. Baker, Tammee M. Parsons, Monica Castanedes-Casey, Virginia Phillips, Ariston L. Librero, Aishe Kurti, John D. Fryer, Guojun Bu, Cathleen Lutz, Dennis W. Dickson, Rosa Rademakers

Research output: Contribution to journalArticle

2 Scopus citations

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−/− mice, suggesting that lowering TMEM106B might be an attractive strategy for therapeutic treatment of FTLD-GRN. Here, we generate and characterize older Tmem106b−/−Grn−/− 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−/−, Tmem106b−/−Grn−/− 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.

Original languageEnglish (US)
JournalEMBO Reports
DOIs
StateAccepted/In press - 2020

Keywords

  • Tdp-43
  • Tmem106b
  • frontotemporal lobar degeneration
  • lysosomes
  • progranulin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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    Zhou, X., Brooks, M., Jiang, P., Koga, S., Zuberi, A. R., Baker, M. C., Parsons, T. M., Castanedes-Casey, M., Phillips, V., Librero, A. L., Kurti, A., Fryer, J. D., Bu, G., Lutz, C., Dickson, D. W., & Rademakers, R. (Accepted/In press). Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice. EMBO Reports. https://doi.org/10.15252/embr.202050197