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Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD

Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to...

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Autores principales: Ward, Michael E., Taubes, Alice, Chen, Robert, Miller, Bruce L., Sephton, Chantelle F., Gelfand, Jeffrey M., Minami, Sakura, Boscardin, John, Martens, Lauren Herl, Seeley, William W., Yu, Gang, Herz, Joachim, Filiano, Anthony J., Arrant, Andrew E., Roberson, Erik D., Kraft, Timothy W., Farese, Robert V., Green, Ari, Gan, Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172214/
https://www.ncbi.nlm.nih.gov/pubmed/25155018
http://dx.doi.org/10.1084/jem.20140214
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author Ward, Michael E.
Taubes, Alice
Chen, Robert
Miller, Bruce L.
Sephton, Chantelle F.
Gelfand, Jeffrey M.
Minami, Sakura
Boscardin, John
Martens, Lauren Herl
Seeley, William W.
Yu, Gang
Herz, Joachim
Filiano, Anthony J.
Arrant, Andrew E.
Roberson, Erik D.
Kraft, Timothy W.
Farese, Robert V.
Green, Ari
Gan, Li
author_facet Ward, Michael E.
Taubes, Alice
Chen, Robert
Miller, Bruce L.
Sephton, Chantelle F.
Gelfand, Jeffrey M.
Minami, Sakura
Boscardin, John
Martens, Lauren Herl
Seeley, William W.
Yu, Gang
Herz, Joachim
Filiano, Anthony J.
Arrant, Andrew E.
Roberson, Erik D.
Kraft, Timothy W.
Farese, Robert V.
Green, Ari
Gan, Li
author_sort Ward, Michael E.
collection PubMed
description Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of familial FTLD-TDP. Grn-KO mice were developed as an FTLD model, but lack cortical TDP-43 mislocalization and neurodegeneration. Here, we report retinal thinning as an early disease phenotype in humans with GRN mutations that precedes dementia onset and an age-dependent retinal neurodegenerative phenotype in Grn-KO mice. Retinal neuron loss in Grn-KO mice is preceded by nuclear depletion of TDP-43 and accompanied by reduced expression of the small GTPase Ran, which is a master regulator of nuclear import required for nuclear localization of TDP-43. In addition, TDP-43 regulates Ran expression, likely via binding to its 3′-UTR. Augmented expression of Ran in progranulin-deficient neurons restores nuclear TDP-43 levels and improves their survival. Our findings establish retinal neurodegeneration as a new phenotype in progranulin-deficient FTLD, and suggest a pathological loop involving reciprocal loss of Ran and nuclear TDP-43 as an underlying mechanism.
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spelling pubmed-41722142015-03-22 Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD Ward, Michael E. Taubes, Alice Chen, Robert Miller, Bruce L. Sephton, Chantelle F. Gelfand, Jeffrey M. Minami, Sakura Boscardin, John Martens, Lauren Herl Seeley, William W. Yu, Gang Herz, Joachim Filiano, Anthony J. Arrant, Andrew E. Roberson, Erik D. Kraft, Timothy W. Farese, Robert V. Green, Ari Gan, Li J Exp Med Brief Definitive Report Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of familial FTLD-TDP. Grn-KO mice were developed as an FTLD model, but lack cortical TDP-43 mislocalization and neurodegeneration. Here, we report retinal thinning as an early disease phenotype in humans with GRN mutations that precedes dementia onset and an age-dependent retinal neurodegenerative phenotype in Grn-KO mice. Retinal neuron loss in Grn-KO mice is preceded by nuclear depletion of TDP-43 and accompanied by reduced expression of the small GTPase Ran, which is a master regulator of nuclear import required for nuclear localization of TDP-43. In addition, TDP-43 regulates Ran expression, likely via binding to its 3′-UTR. Augmented expression of Ran in progranulin-deficient neurons restores nuclear TDP-43 levels and improves their survival. Our findings establish retinal neurodegeneration as a new phenotype in progranulin-deficient FTLD, and suggest a pathological loop involving reciprocal loss of Ran and nuclear TDP-43 as an underlying mechanism. The Rockefeller University Press 2014-09-22 /pmc/articles/PMC4172214/ /pubmed/25155018 http://dx.doi.org/10.1084/jem.20140214 Text en © 2014 Ward et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Ward, Michael E.
Taubes, Alice
Chen, Robert
Miller, Bruce L.
Sephton, Chantelle F.
Gelfand, Jeffrey M.
Minami, Sakura
Boscardin, John
Martens, Lauren Herl
Seeley, William W.
Yu, Gang
Herz, Joachim
Filiano, Anthony J.
Arrant, Andrew E.
Roberson, Erik D.
Kraft, Timothy W.
Farese, Robert V.
Green, Ari
Gan, Li
Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD
title Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD
title_full Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD
title_fullStr Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD
title_full_unstemmed Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD
title_short Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD
title_sort early retinal neurodegeneration and impaired ran-mediated nuclear import of tdp-43 in progranulin-deficient ftld
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172214/
https://www.ncbi.nlm.nih.gov/pubmed/25155018
http://dx.doi.org/10.1084/jem.20140214
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