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

• Published in: The Journal of experimental medicine Vol. 211; no. 10; pp. 1937 - 1945
• Main Authors: 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, Jr, Robert V, Green, Ari, Gan, Li
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 22-09-2014
• Subjects: Active Transport, Cell Nucleus - physiology; Age Factors; Animals; Brief Definitive Report; DNA-Binding Proteins - metabolism; Electroretinography; Frontotemporal Dementia - complications; Frontotemporal Dementia - genetics; Gene Expression Regulation - physiology; Humans; Intercellular Signaling Peptides and Proteins - genetics; Linear Models; Mice; Mice, Knockout; Mutation - genetics; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - physiopathology; ran GTP-Binding Protein - metabolism; Retina - physiopathology; Tomography, Optical Coherence
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20140214

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.