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


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • September 22, 2014

Published In

Volume / Issue

  • 211 / 10

Start / End Page

  • 1937 - 1945

PubMed ID

  • 25155018

Pubmed Central ID

  • 25155018

Electronic International Standard Serial Number (EISSN)

  • 1540-9538

Digital Object Identifier (DOI)

  • 10.1084/jem.20140214


  • eng

Conference Location

  • United States