論文 - 詳細
| RRC ID | 88267 |
|---|---|
| 著者 | Klein ZA, Takahashi H, Ma M, Stagi M, Zhou M, Lam TT, Strittmatter SM. |
| タイトル | Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. |
| ジャーナル | Neuron |
| Abstract |
Progranulin (GRN) and TMEM106B are associated with several common neurodegenerative disorders including frontotemporal lobar degeneration (FTLD). A TMEM106B variant modifies GRN-associated FTLD risk. However, their functional relationship in vivo and the mechanisms underlying the risk modification remain unclear. Here, using transcriptomic and proteomic analyses with Grn-/- and Tmem106b-/- mice, we show that, while multiple lysosomal enzymes are increased in Grn-/- brain at both transcriptional and protein levels, TMEM106B deficiency causes reduction in several lysosomal enzymes. Remarkably, Tmem106b deletion from Grn-/- mice normalizes lysosomal protein levels and rescues FTLD-related behavioral abnormalities and retinal degeneration without improving lipofuscin, C1q, and microglial accumulation. Mechanistically, TMEM106B binds vacuolar-ATPase accessory protein 1 (AP1). TMEM106B deficiency reduces vacuolar-ATPase AP1 and V0 subunits, impairing lysosomal acidification and normalizing lysosomal protein levels in Grn-/- neurons. Thus, Grn and Tmem106b genes have opposite effects on lysosomal enzyme levels, and their interaction determines the extent of neurodegeneration. |
| 巻・号 | 95(2) |
| ページ | 281-296.e6 |
| 公開日 | 2017-7-19 |
| DOI | 10.1016/j.neuron.2017.06.026 |
| PII | S0896-6273(17)30550-0 |
| PMID | 28728022 |
| PMC | PMC5558861 |
| MeSH | Animals Brain / metabolism Cells, Cultured Frontotemporal Dementia / genetics* Granulins Intercellular Signaling Peptides and Proteins / deficiency* Lysosomes / genetics Lysosomes / metabolism Mice, Knockout Mutation / genetics* Neurons / metabolism Phenotype Polymorphism, Single Nucleotide / genetics Progranulins Proteomics |
| IF | 14.415 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 21 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC02370 |