Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice.



Zoe Klein, , Hideyuki Takahashi, , Mengxiao Ma, , Massimiliano Stagi, , Melissa Zhou, , TuKiet Lam, and Stephen M. Strittmatter,
(2017) Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. Neuron, 95 (2). pp. 281-296.

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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.

Item Type: Article
Uncontrolled Keywords: frontotemporal lobar degeneration, dementia, Progranulin, TMEM106B, lysosome, retinal degradation, vacuolar ATPase
Depositing User: Symplectic Admin
Date Deposited: 26 Jun 2017 07:08
Last Modified: 19 Jan 2023 07:02
DOI: 10.1016/j.neuron.2017.06.026
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3008129