title: Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency.
abstract: Mutations resulting in haploinsufficiency of progranulin (PGRN) cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. Accumulating evidence suggest a crucial role of progranulin in maintaining proper lysosomal function during aging. TMEM106B has been identified as a risk factor for ﻿frontotemporal lobar degeneration ﻿with progranulin mutations and elevated mRNA and protein levels of TMEM106B are associated with increased risk for frontotemporal lobar degeneration. Increased levels of TMEM106B alter lysosomal morphology and interfere with lysosomal degradation. However, how progranulin and TMEM106B interact to regulate lysosomal function and frontotemporal lobar degeneration﻿ (FTLD) disease progression is still unclear. Here we report that progranulin deficiency leads to increased TMEM106B protein levels in the mouse cortex with aging. To mimic elevated levels of TMEM106B in frontotemporal lobar degeneration﻿ (FTLD) cases, we generated transgenic mice expressing TMEM106B under the neuronal specific promoter, CamKII. Surprisingly, we found that the total protein levels of TMEM106B are not altered despite the expression of the TMEM106B transgene at mRNA and protein levels, suggesting a tight regulation of TMEM106B protein levels in the mouse brain. However, progranulin deficiency results in accumulation of TMEM106B protein from the transgene expression during aging, which is accompanied by exaggerated lysosomal abnormalities and increased lipofuscin accumulation. In summary, our mouse model nicely recapitulates the interaction between progranulin and TMEM106B in human patients and supports a critical role of lysosomal dysfunction in the frontotemporal lobar degeneration﻿ (FTLD) disease progression.
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, 14853, NY, USA.
authors.forename: Xiaolai
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, 14853, NY, USA.|Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, 14853, NY, USA.
authors.forename: Owen Adam
authors.initials: OA
authors.lastname: Brady
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, 14853, NY, USA.
authors.forename: Kira A
authors.initials: KA
authors.lastname: Murphy
authors.affiliation: Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, 14853, NY, USA. fh87@cornell.edu.
authors.forename: Fenghua
authors.identifier: http://orcid.org/0000-0002-6447-9992
authors.initials: F
authors.lastname: Hu
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D000077155:Granulins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008062:Lipofuscin / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000077153:Progranulins; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008062:Lipofuscin; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; D012333:RNA, Messenger; C556915:TMEM106B protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Frontotemporal lobar degeneration (FTLD); Lipofuscin; Lysosome; Progranulin; TMEM106B