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.

TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy

“…We were even more surprised to discover that this functional protection arose without any obvious change in tau pathology. This outcome is similar to the findings of a recent study testing the T186S variant in a GRN deletion model of FTLD-TDP (Cabron et al, 2023). T186S had no impact on lysosome and lipofuscin accumulation that are pathological hallmarks of GRN deletion, and showed only a limited effect on microgliosis that was restricted to CD68 elevation in the thalamus.…”

“…Unlike TMEM106B deletion, the coding variant had no impact on the transcriptional correlation between mouse tau and human AD. This limited transcriptional effect echoes similar futility with T186S in the GRN null animals (Cabron et al, 2023). Despite this drawback, we were able to mine DEGs using a relaxed cutoff for hints at what might underlie the variant's protective effect.…”

“…Only one study to date has tested the coding variant in vivo with disappointing results. The T186S variant had little impact on pathology or microgliosis with only mild changes in lysosomal enzyme activity and lipid content in a GRN deletion model of FTLD (Cabron et al, 2023). Despite the known association of the protective TMEM106B haplotype and its T185S coding variant with cognitive resilience and neuroprotection, no studies to date have examined these downstream consequences of disease in an experimental model.…”

An AluYb8 retrotransposon characterises a risk haplotype of TMEM106B associated in neurodegeneration

“…Notably, there were no observable functional changes in a CRISPR-based knockin-mouse model homozygous for the T185S substitution 14 .…”

“…However, N- glycosylation sites commonly occur at a N-X-S/T motif, suggesting that substituting the N 183 -I 184 -T 185 motif to N 183 -I 184 -S 185 motif is unlikely to have any effect 19 . Notably, there were no observable functional changes in a CRISPR-based knockin-mouse model homozygous for the T185S substitution 14 .…”