@article{a4e01268507541118944740cbb870822,
title = "Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice",
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.",
keywords = "Tdp-43, Tmem106b, frontotemporal lobar degeneration, lysosomes, progranulin",
author = "Xiaolai Zhou and Mieu Brooks and Peizhou Jiang and Shunsuke Koga and Zuberi, {Aamir R.} and Baker, {Matthew C.} and Parsons, {Tammee M.} and Monica Castanedes-Casey and Virginia Phillips and Librero, {Ariston L.} and Aishe Kurti and Fryer, {John D.} and Guojun Bu and Cathleen Lutz and Dickson, {Dennis W.} and Rosa Rademakers",
note = "Funding Information: RR received funding from the National Institutes of Health (NIH) (grant R35 NS097261) and the Bluefield Project to Cure FTLD. The generation of the CRISP/Cas9 knockout mouse model at The Jackson Laboratory was supported by The Center for Precision Genetics, NIH U54 OD020351, and partially supported by the Jackson Laboratory's Genetic Engineering Technologies Scientific Service. XZ is supported by a research fellowship from The Bluefield Project to Cure FTD and a Developmental Grant from the Mayo Clinic ADRC (NIH P30 AG062677). Tmem106b Funding Information: RR received funding from the National Institutes of Health (NIH) (grant R35 NS097261) and the Bluefield Project to Cure FTLD. The generation of the CRISP/Cas9 Tmem106b knockout mouse model at The Jackson Laboratory was supported by The Center for Precision Genetics, NIH U54 OD020351, and partially supported by the Jackson Laboratory's Genetic Engineering Technologies Scientific Service. XZ is supported by a research fellowship from The Bluefield Project to Cure FTD and a Developmental Grant from the Mayo Clinic ADRC (NIH P30 AG062677). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = oct,
day = "5",
doi = "10.15252/embr.202050197",
language = "English (US)",
volume = "21",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "10",
}