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

Michael E. Ward, Alice Taubes, Robert Chen, Bruce L. Miller, Chantelle F. Sephton, Jeffrey M. Gelfand, Sakura Minami, John Boscardin, Lauren Herl Martens, William W. Seeley, Gang Yu, Joachim Herz, Anthony J. Filiano, Andrew E. Arrant, Erik D. Roberson, Timothy W. Kraft, Robert V. Farese, Ari Green, Li Gan

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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 progranulindeficient 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.

Original languageEnglish (US)
Pages (from-to)1937-1945
Number of pages9
JournalJournal of Experimental Medicine
Volume211
Issue number10
DOIs
StatePublished - 2014

Fingerprint

Frontotemporal Lobar Degeneration
Cell Nucleus Active Transport
DNA-Binding Proteins
Frontotemporal Dementia
Phenotype
Dementia
Retinal Neurons
Mutation
Monomeric GTP-Binding Proteins
3' Untranslated Regions
trans-activation responsive RNA-binding protein
Age of Onset
Neurons
Survival

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Ward, M. E., Taubes, A., Chen, R., Miller, B. L., Sephton, C. F., Gelfand, J. M., ... Gan, L. (2014). Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. Journal of Experimental Medicine, 211(10), 1937-1945. https://doi.org/10.1084/jem.20140214

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.

In: Journal of Experimental Medicine, Vol. 211, No. 10, 2014, p. 1937-1945.

Research output: Contribution to journalArticle

Ward, ME, Taubes, A, Chen, R, Miller, BL, Sephton, CF, Gelfand, JM, Minami, S, Boscardin, J, Martens, LH, Seeley, WW, Yu, G, Herz, J, Filiano, AJ, Arrant, AE, Roberson, ED, Kraft, TW, Farese, RV, Green, A & Gan, L 2014, 'Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD', Journal of Experimental Medicine, vol. 211, no. 10, pp. 1937-1945. https://doi.org/10.1084/jem.20140214
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. In: Journal of Experimental Medicine. 2014 ; Vol. 211, No. 10. pp. 1937-1945.
@article{70c0e98a89374f18ba4df1b11ccfa2ac,
title = "Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD",
abstract = "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 progranulindeficient 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.",
author = "Ward, {Michael E.} and Alice Taubes and Robert Chen and Miller, {Bruce L.} and Sephton, {Chantelle F.} and Gelfand, {Jeffrey M.} and Sakura Minami and John Boscardin and Martens, {Lauren Herl} and Seeley, {William W.} and Gang Yu and Joachim Herz and Filiano, {Anthony J.} and Arrant, {Andrew E.} and Roberson, {Erik D.} and Kraft, {Timothy W.} and Farese, {Robert V.} and Ari Green and Li Gan",
year = "2014",
doi = "10.1084/jem.20140214",
language = "English (US)",
volume = "211",
pages = "1937--1945",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "10",

}

TY - JOUR

T1 - Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD

AU - Ward, Michael E.

AU - Taubes, Alice

AU - Chen, Robert

AU - Miller, Bruce L.

AU - Sephton, Chantelle F.

AU - Gelfand, Jeffrey M.

AU - Minami, Sakura

AU - Boscardin, John

AU - Martens, Lauren Herl

AU - Seeley, William W.

AU - Yu, Gang

AU - Herz, Joachim

AU - Filiano, Anthony J.

AU - Arrant, Andrew E.

AU - Roberson, Erik D.

AU - Kraft, Timothy W.

AU - Farese, Robert V.

AU - Green, Ari

AU - Gan, Li

PY - 2014

Y1 - 2014

N2 - 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 progranulindeficient 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.

AB - 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 progranulindeficient 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.

UR - http://www.scopus.com/inward/record.url?scp=84907212776&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907212776&partnerID=8YFLogxK

U2 - 10.1084/jem.20140214

DO - 10.1084/jem.20140214

M3 - Article

VL - 211

SP - 1937

EP - 1945

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 10

ER -