| First Author | Klein ZA | Year | 2017 |
| Journal | Neuron | Volume | 95 |
| Issue | 2 | Pages | 281-296.e6 |
| PubMed ID | 28728022 | Mgi Jnum | J:250046 |
| Mgi Id | MGI:6101836 | Doi | 10.1016/j.neuron.2017.06.026 |
| Citation | Klein ZA, et al. (2017) Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. Neuron 95(2):281-296.e6 |
| abstractText | 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. |
