Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration
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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, Vol. 11, No. 1, 21, 27.01.2023.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -