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Title
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Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice
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Author
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Abstract
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| 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 ofFTLD, whileTMEM106Bvariants have been shown to act as disease modifiers inFTLD. Overexpression ofTMEM106B leads to lysosomal dysfunction, while loss of Tmem106b ameliorates lysosomal andFTLD-related pathologies in youngGrn(-/-)mice, suggesting that loweringTMEM106B might be an attractive strategy for therapeutic treatment ofFTLD-GRN. Here, we generate and characterize olderTmem106b(-/-)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 toGrn(-/-),Tmem106b(-/-)Grn(-/-)mice have exacerbatedFTLD-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 modulatingTMEM106B levels is a viable therapeutic strategy. |
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Language
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English
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Source (journal)
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EMBO reports. - Oxford, 2000, currens
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Publication
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Oxford
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2020
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ISSN
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1469-221X
[print]
1469-3178
[online]
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DOI
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10.15252/EMBR.202050197
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Volume/pages
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21
:10
(2020)
, 14 p.
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Article Reference
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e50197
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ISI
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000555807900001
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Pubmed ID
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32761777
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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