期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 10, 页码 1937-1945出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20140214
关键词
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资金
- Consortium for Frontotemporal Dementia Research
- Bluefield Project to Cure FTD [R01 AG036884]
- UCSF Resource Allocation Program
- UCSF Alzheimer's Disease Research Center [P50 AG023501, R01NS079796, R01NS075487, T32HD071866, K08EY023610]
- Chartrand Foundation
- Howard Hughes Medical Institute
- Alzheimer's Association
- Welch Foundation [R37HL63762]
- Brightfocus Foundation
- Alzheimer's Drug Discovery Foundation
- Clinical & Science Translational Institute
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.
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