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

Journal Article (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

  • PMC4172214

Electronic International Standard Serial Number (EISSN)

  • 1540-9538

Digital Object Identifier (DOI)

  • 10.1084/jem.20140214


  • eng

Conference Location

  • United States