Journal
NEURON
Volume 95, Issue 2, Pages 281-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2017.06.026
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Funding
- Yale University School of Medicine
- NIH [R01NS074319, R35NS097283, R01AG037924, P50AG047270]
- Falk Medical Research Trust
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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.
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