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

TitleEarly retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD.
Publication TypeJournal Article
Year of Publication2014
AuthorsWard ME, Taubes A, Chen R, Miller BL, Sephton CF, Gelfand JM, Minami S, Boscardin J, Martens LHerl, Seeley WW, Yu G, Herz J, Filiano AJ, Arrant AE, Roberson ED, Kraft TW, Farese RV, Green A, Gan L
JournalJ Exp Med
Date Published2014 Sep 22
KeywordsActive Transport, Cell Nucleus, Age Factors, Animals, DNA-Binding Proteins, Electroretinography, Frontotemporal Dementia, Gene Expression Regulation, Humans, Intercellular Signaling Peptides and Proteins, Linear Models, Mice, Mice, Knockout, Mutation, Neurodegenerative Diseases, ran GTP-Binding Protein, Retina, Tomography, Optical Coherence

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.

Alternate JournalJ. Exp. Med.
PubMed ID25155018
PubMed Central IDPMC4172214
Grant ListR01 NS079796 / NS / NINDS NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
T32 HD071866 / HD / NICHD NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
R01 NS075487 / NS / NINDS NIH HHS / United States
R37 HL063762 / HL / NHLBI NIH HHS / United States
K08 EY023610 / EY / NEI NIH HHS / United States