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Open Access 01-12-2023 | Research

Lack of a protective effect of the Tmem106b “protective SNP” in the Grn knockout mouse model for frontotemporal lobar degeneration

Authors: Anne-Sophie Cabron, Uwe Borgmeyer, Julia Richter, Helga Peisker, Katharina Gutbrod, Peter Dörmann, Anja Capell, Markus Damme

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

Genetic variants in TMEM106B are a common risk factor for frontotemporal lobar degeneration and the most important modifier of disease risk in patients with progranulin (GRN) mutations (FTLD-GRN). TMEM106B is encoding a lysosomal transmembrane protein of unknown molecular function. How it mediates its disease-modifying function remains enigmatic. Several TMEM106B single nucleotide polymorphisms (SNPs) are significantly associated with disease risk in FTLD-GRN carriers, of which all except one are within intronic sequences of TMEM106B. Of note, the non-coding SNPs are in high linkage disequilibrium with the coding SNP rs3173615 located in exon six of TMEM106B, resulting in a threonine to serine change at amino acid 185 in the minor allele, which is protective in FTLD-GRN carriers. To investigate the functional consequences of this variant in vivo, we generated and characterized a knockin mouse model harboring the Tmem106b^T186S variant. We analyzed the effect of this protective variant on FTLD pathology by crossing Tmem106b^T186S mice with Grn^−/− knockout mice, a model for GRN-mediated FTLD. We did not observe the amelioration of any of the investigated Grn^−/− knockout phenotypes, including transcriptomic changes, lipid alterations, or microgliosis in Tmem106b^T186S/T186S × Grn^−/− mice, indicating that the Tmem106b^T186S variant is not protective in the Grn^−/− knockout mouse model. These data suggest that effects of the associated SNPs not directly linked to the amino acid exchange in TMEM106B are critical for the modifying effect.

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Title: Lack of a protective effect of the Tmem106b “protective SNP” in the Grn knockout mouse model for frontotemporal lobar degeneration
Authors: Anne-Sophie Cabron
Uwe Borgmeyer
Julia Richter
Helga Peisker
Katharina Gutbrod
Peter Dörmann
Anja Capell
Markus Damme
Publication date: 01-12-2023
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01510-3

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Lack of a protective effect of the Tmem106b “protective SNP” in the Grn knockout mouse model for frontotemporal lobar degeneration

Abstract

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Abstract

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