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J Exp Med. 2014 Sep 22;211(10):1937-45. doi: 10.1084/jem.20140214. Epub 2014 Aug 25.

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

Author information

1
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.
2
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.
3
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.
4
Departments of Neurology and Neurobiology and Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL 35294.
5
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.

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.

PMID:
25155018
PMCID:
PMC4172214
DOI:
10.1084/jem.20140214
[Indexed for MEDLINE]
Free PMC Article

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