TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models.

Autor:	Dominguez SL; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA., Laufer BI; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA.; Department of OMNI Bioinformatics, Genentech, South San Francisco, CA 94080, USA., Ghosh AS; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA., Li Q; Department of Microchemistry, Proteomics, and Lipidomics, Genentech, South San Francisco, CA 94080, USA., Ruggeri G; Department of Biochemistry and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA., Emani MR; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA.; Department of Biochemistry and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA., Phu L; Department of Microchemistry, Proteomics, and Lipidomics, Genentech, South San Francisco, CA 94080, USA., Friedman BA; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA.; Department of OMNI Bioinformatics, Genentech, South San Francisco, CA 94080, USA., Sandoval W; Department of Microchemistry, Proteomics, and Lipidomics, Genentech, South San Francisco, CA 94080, USA., Rose CM; Department of Microchemistry, Proteomics, and Lipidomics, Genentech, South San Francisco, CA 94080, USA., Ngu H; Department of Pathology, Genentech, South San Francisco, CA 94080, USA., Foreman O; Department of Pathology, Genentech, South San Francisco, CA 94080, USA., Reichelt M; Department of Pathology, Genentech, South San Francisco, CA 94080, USA., Juste Y; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA., Lalehzadeh G; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA., Hansen D; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Copenhagen, 2970 Hørsholm, DK, Denmark., Nymark H; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Copenhagen, 2970 Hørsholm, DK, Denmark., Mellal D; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Copenhagen, 2970 Hørsholm, DK, Denmark., Gylling H; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Copenhagen, 2970 Hørsholm, DK, Denmark., Kiełpiński ŁJ; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Copenhagen, 2970 Hørsholm, DK, Denmark., Chih B; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA.; Department of Biochemistry and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA., Bingol B; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA., Hoogenraad CC; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA., Meilandt WJ; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA., Easton A; Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2023 Oct 29; Vol. 26 (11), pp. 108362. Date of Electronic Publication: 2023 Oct 29 (Print Publication: 2023).
DOI:	10.1016/j.isci.2023.108362
Abstrakt:	Heterozygous mutations in the granulin ( GRN ) gene are a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in TMEM106B have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here, we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. TMEM106B deletion did not reverse transcriptomic or proteomic profiles in GRN-deficient microglia, with a few exceptions in immune signaling markers. Neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated phenotypes in Grn -/- mice. Furthermore, Tmem106b reduction by antisense oligonucleotide (ASO) was poorly tolerated in Grn -/- mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTD- GRN . Competing Interests: The authors have a published patent application WO 2019/154979 A1 related to this work. (© 2023 The Authors.)
Databáze:	MEDLINE
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