Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice.

Autor: Werner G; Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany., Damme M; Institute of Biochemistry, Kiel University, Kiel, Germany., Schludi M; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Gnörich J; Department of Nuclear Medicine, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Wind K; Department of Nuclear Medicine, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Fellerer K; Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany., Wefers B; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Wurst W; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Edbauer D; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Brendel M; Department of Nuclear Medicine, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany., Haass C; Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Capell A; Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
Jazyk: angličtina
Zdroj: EMBO reports [EMBO Rep] 2020 Oct 05; Vol. 21 (10), pp. e50241. Date of Electronic Publication: 2020 Sep 14.
DOI: 10.15252/embr.202050241
Abstrakt: Single nucleotide polymorphisms (SNPs) in TMEM106B encoding the lysosomal type II transmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN (progranulin gene) mutation carriers. Currently, it is unclear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss of function of TMEM106B is responsible for the increased disease risk of patients with GRN haploinsufficiency. We therefore compare behavioral abnormalities, gene expression patterns, lysosomal activity, and TDP-43 pathology in single and double knockout animals. Grn -/- /Tmem106b -/- mice show a strongly reduced life span and massive motor deficits. Gene expression analysis reveals an upregulation of molecular signature characteristic for disease-associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as an accumulation of ubiquitinated proteins and widespread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn -/- knockouts only occasionally show TDP-43 pathology, the double knockout mice exhibit deposition of phosphorylated TDP-43. Thus, a loss of function of TMEM106B may enhance the risk for GRN-associated FTLD by reduced protein turnover in the lysosomal/autophagic system.
(© 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
Databáze: MEDLINE
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