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 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.
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158 Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Ward
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: Alice
authors.initials: A
authors.lastname: Taubes
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: Robert
authors.initials: R
authors.lastname: Chen
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Chantelle F
authors.initials: CF
authors.lastname: Sephton
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gelfand
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: Sakura
authors.initials: S
authors.lastname: Minami
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: John
authors.initials: J
authors.lastname: Boscardin
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: Lauren Herl
authors.initials: LH
authors.lastname: Martens
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: Departments of Neurology and Neurobiology and Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Filiano
authors.affiliation: Departments of Neurology and Neurobiology and Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Arrant
authors.affiliation: Departments of Neurology and Neurobiology and Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Erik D
authors.initials: ED
authors.lastname: Roberson
authors.affiliation: Departments of Neurology and Neurobiology and Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Kraft
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158.
authors.forename: Ari
authors.initials: A
authors.lastname: Green
authors.affiliation: Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158 Gladstone Institute of Neurological Diseases, Department of Neurology, Department of Medicine, Gladstone Institute of Cardiovascular Disease, University of California, San Franciso, San Francisco, CA 94158 agreen@ucsf.edu lgan@gladstone.ucsf.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Gan
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000367:Age Factors; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004596:Electroretinography; D057180:Frontotemporal Dementia / Q000150:complications* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D000077155:Granulins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D016014:Linear Models; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000503:physiopathology*; D000077153:Progranulins; D012160:Retina / Q000503:physiopathology*; D041623:Tomography, Optical Coherence; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D020931:ran GTP-Binding Protein; C120204:Grn protein, mouse; C102460:Ran protein, mouse; C578077:Tardbp protein, mouse