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

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.
AuthorsZoe A Klein, Hideyuki Takahashi, Mengxiao Ma, Massimiliano Stagi, Melissa Zhou, TuKiet T Lam, Stephen M Strittmatter
JournalNeuron (Neuron) Vol. 95 Issue 2 Pg. 281-296.e6 (Jul 19 2017) ISSN: 1097-4199 [Electronic] United States
PMID28728022 (Publication Type: Journal Article)
CopyrightCopyright © 2017 Elsevier Inc. All rights reserved.
Chemical References
  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
Topics
  • Animals
  • Brain (metabolism)
  • Cells, Cultured
  • Frontotemporal Dementia (genetics)
  • Granulins
  • Intercellular Signaling Peptides and Proteins (deficiency)
  • Lysosomes (genetics, metabolism)
  • Mice, Knockout
  • Mutation (genetics)
  • Neurons (metabolism)
  • Phenotype
  • Polymorphism, Single Nucleotide (genetics)
  • Progranulins
  • Proteomics

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