Loss of Tmem106b exacerbatesFTLDpathologies and causes motor deficits in progranulin-deficient mice

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.