| Autor: |
Anne-Sophie Cabron, Uwe Borgmeyer, Julia Richter, Helga Peisker, Katharina Gutbrod, Peter Dörmann, Anja Capell, Markus Damme |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Acta Neuropathologica Communications, Vol 11, Iss 1, Pp 1-13 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2051-5960 |
| DOI: |
10.1186/s40478-023-01510-3 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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