TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Mouse ASO]
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ABSTRACT: Heterozygous mutations in the granulin (GRN) gene result in haploinsufficiency of the progranulin (PGRN) protein, a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in the TMEM106B gene have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants are 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. In vitro, TMEM106B deletion did not reverse transcriptomic and proteomic profiles in GRN-deficient microglia, with the exception of a small set of immune-related proteins in the NF-κB pathway. In vivo, neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated gene expression in sorted microglia, lipid abnormalities, or histopathology in Grn knock-out mice. Furthermore, Tmem106b reduction with antisense oligonucleotide (ASO) treatment was poorly tolerated in Grn knock-out 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 FTLD-GRN.
ORGANISM(S): Mus musculus
PROVIDER: GSE237105 | GEO | 2023/11/15
REPOSITORIES: GEO
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