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

Standard

Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration. / Cabron, Anne-Sophie; Borgmeyer, Uwe; Richter, Julia; Peisker, Helga; Gutbrod, Katharina; Dörmann, Peter; Capell, Anja; Damme, Markus.

in: ACTA NEUROPATHOL COM, Jahrgang 11, Nr. 1, 21, 27.01.2023.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Cabron, A-S, Borgmeyer, U, Richter, J, Peisker, H, Gutbrod, K, Dörmann, P, Capell, A & Damme, M 2023, 'Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration', ACTA NEUROPATHOL COM, Jg. 11, Nr. 1, 21. https://doi.org/10.1186/s40478-023-01510-3

APA

Cabron, A-S., Borgmeyer, U., Richter, J., Peisker, H., Gutbrod, K., Dörmann, P., Capell, A., & Damme, M. (2023). Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration. ACTA NEUROPATHOL COM, 11(1), [21]. https://doi.org/10.1186/s40478-023-01510-3

Vancouver

Cabron A-S, Borgmeyer U, Richter J, Peisker H, Gutbrod K, Dörmann P et al. Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration. ACTA NEUROPATHOL COM. 2023 Jan 27;11(1). 21. https://doi.org/10.1186/s40478-023-01510-3

Bibtex

@article{28066f85b43941e09f6469ca707da9bb,
title = "Lack of a protective effect of the Tmem106b {"}protective SNP{"} in the Grn knockout mouse model for frontotemporal lobar degeneration",
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 Tmem106bT186S variant. We analyzed the effect of this protective variant on FTLD pathology by crossing Tmem106bT186S 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 Tmem106bT186S/T186S × Grn-/- mice, indicating that the Tmem106bT186S 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.",
keywords = "Animals, Mice, Amino Acids, Frontotemporal Dementia/genetics, Frontotemporal Lobar Degeneration/pathology, Intercellular Signaling Peptides and Proteins/genetics, Membrane Proteins/genetics, Mice, Knockout, Mutation, Nerve Tissue Proteins/genetics, Polymorphism, Single Nucleotide/genetics",
author = "Anne-Sophie Cabron and Uwe Borgmeyer and Julia Richter and Helga Peisker and Katharina Gutbrod and Peter D{\"o}rmann and Anja Capell and Markus Damme",
note = "{\textcopyright} 2023. The Author(s).",
year = "2023",
month = jan,
day = "27",
doi = "10.1186/s40478-023-01510-3",
language = "English",
volume = "11",
journal = "ACTA NEUROPATHOL COM",
issn = "2051-5960",
publisher = "BioMed Central Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration

AU - Cabron, Anne-Sophie

AU - Borgmeyer, Uwe

AU - Richter, Julia

AU - Peisker, Helga

AU - Gutbrod, Katharina

AU - Dörmann, Peter

AU - Capell, Anja

AU - Damme, Markus

N1 - © 2023. The Author(s).

PY - 2023/1/27

Y1 - 2023/1/27

N2 - 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 Tmem106bT186S variant. We analyzed the effect of this protective variant on FTLD pathology by crossing Tmem106bT186S 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 Tmem106bT186S/T186S × Grn-/- mice, indicating that the Tmem106bT186S 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.

AB - 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 Tmem106bT186S variant. We analyzed the effect of this protective variant on FTLD pathology by crossing Tmem106bT186S 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 Tmem106bT186S/T186S × Grn-/- mice, indicating that the Tmem106bT186S 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.

KW - Animals

KW - Mice

KW - Amino Acids

KW - Frontotemporal Dementia/genetics

KW - Frontotemporal Lobar Degeneration/pathology

KW - Intercellular Signaling Peptides and Proteins/genetics

KW - Membrane Proteins/genetics

KW - Mice, Knockout

KW - Mutation

KW - Nerve Tissue Proteins/genetics

KW - Polymorphism, Single Nucleotide/genetics

U2 - 10.1186/s40478-023-01510-3

DO - 10.1186/s40478-023-01510-3

M3 - SCORING: Journal article

C2 - 36707901

VL - 11

JO - ACTA NEUROPATHOL COM

JF - ACTA NEUROPATHOL COM

SN - 2051-5960

IS - 1

M1 - 21

ER -