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Neuron. 2017 Jul 19;95(2):281-296.e6. doi: 10.1016/j.neuron.2017.06.026.

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

Author information

1
Program in Cellular Neuroscience, Neurodegeneration & Repair, Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT 06536, USA.
2
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; MS & Proteomics Resource, WM Keck Biotechnology Resource Laboratory, New Haven, CT 06511, USA.
3
Program in Cellular Neuroscience, Neurodegeneration & Repair, Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT 06536, USA. Electronic address: stephen.strittmatter@yale.edu.

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.

KEYWORDS:

Progranulin; TMEM106B; dementia; frontotemporal lobar degeneration; lysosome; retinal degradation; vacuolar ATPase

PMID:
28728022
PMCID:
PMC5558861
DOI:
10.1016/j.neuron.2017.06.026
[Indexed for MEDLINE]
Free PMC Article

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