Microglial activation in an amyotrophic lateral sclerosis-like model caused by Ranbp2 loss and nucleocytoplasmic transport impairment in retinal ganglion neurons

Abstract

Nucleocytoplasmic transport is dysregulated in sporadic and familial amyotrophic lateral sclerosis (ALS) and retinal ganglion neurons (RGNs) are purportedly involved in ALS. The Ran-binding protein 2 (Ranbp2) controls rate-limiting steps of nucleocytoplasmic transport. Mice with Ranbp2 loss in Thy1+-motoneurons develop cardinal ALS-like motor traits, but the impairments in RGNs and the degree of dysfunctional consonance between RGNs and motoneurons caused by Ranbp2 loss are unknown. This will help to understand the role of nucleocytoplasmic transport in the differential vulnerability of neuronal cell types to ALS and to uncover non-motor endophenotypes with pathognomonic signs of ALS. Here, we ascertain Ranbp2’s function and endophenotypes in RGNs of an ALS-like mouse model lacking Ranbp2 in motoneurons and RGNs. Thy1+-RGNs lacking Ranbp2 shared with motoneurons the dysregulation of nucleocytoplasmic transport. RGN abnormalities were comprised morphologically by soma hypertrophy and optic nerve axonopathy and physiologically by a delay of the visual pathway’s evoked potentials. Whole-transcriptome analysis showed restricted transcriptional changes in optic nerves that were distinct from those found in sciatic nerves. Specifically, the level and nucleocytoplasmic partition of the anti-apoptotic and novel substrate of Ranbp2, Pttg1/securin, were dysregulated. Further, acetyl-CoA carboxylase 1, which modulates de novo synthesis of fatty acids and T-cell immunity, showed the highest up-regulation (35-fold). This effect was reflected by the activation of ramified CD11b+ and CD45+-microglia, increase of F4\80+-microglia and a shift from pseudopodial/lamellipodial to amoeboidal F4\80+-microglia intermingled between RGNs of naive mice. Further, there was the intracellular sequestration in RGNs of metalloproteinase-28, which regulates macrophage recruitment and polarization in inflammation. Hence, Ranbp2 genetic insults in RGNs and motoneurons trigger distinct paracrine signaling likely by the dysregulation of nucleocytoplasmic transport of neuronal-type selective substrates. Immune-modulators underpinning RGN-to-microglial signaling are regulated by Ranbp2, and this neuronal-glial system manifests endophenotypes that are likely useful in the prognosis and diagnosis of motoneuron diseases, such as ALS.

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Acknowledgements

We thank Guoping Feng (MIT, Cambridge, MA) for SLICK-H mice, Ian Macara (Vanderbilt University, Nashville, TN) for the antibody against Ran-GTP, Sandra Stinnett for help with statistical analyses of RGN morphometry (Duke University, Durham, NC), Ying Hao for help with the processing of the specimens for transmission electron microscopy (Duke University, Durham, NC).

Funding

The study was funded by National Institutes of Health Grants GM083165, GM083165-03S1 and EY019492 to P.A.F. This work was also supported by a Core Grant (P30 EY025585) to Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and a Research Career Scientist Award to N.S.P. from the U.S. Department of Veterans Affairs.

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Contributions

KC and PAF conceived and supervised the study; KC, NSP and PAF designed experiments; KC, MY and DY performed experiments; PAF provided new tools and reagents; KC, DY, NPS and PAF analyzed data; KC and PAF wrote the manuscript.

Corresponding author

Correspondence to Paulo A. Ferreira.

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Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. All authors consent for the publication of this study.

Availability of data and materials

The datasets supporting the conclusions of this article are available in the Sequence Reads Archives (SRA; https://www.ncbi.nlm.nih.gov/sra) of the National Center for Biotechnology Information (NCBI) with the accession number: SRP139153. Datasets of a total of ~ 17.4 billion bases of unprocessed RNA sequencing were deposited as FASTq files at the SRA. The project overview was deposited with the Bioproject accession number: PRJNA449172. The optic nerves of SLICK-H::Ranbp2+/+, SLICK-H::Ranbp2flox/flox and Tg-RBD2/3*-HA::SLICK-H::Ranbp2flox/flox have the respective biosamples accession numbers: SAMN08891694, SAMN08891693 and SAMN08891695. Other datasets and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Cho, K., Yoon, D., Yu, M. et al. Microglial activation in an amyotrophic lateral sclerosis-like model caused by Ranbp2 loss and nucleocytoplasmic transport impairment in retinal ganglion neurons. Cell. Mol. Life Sci. 76, 3407–3432 (2019). https://doi.org/10.1007/s00018-019-03078-5

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Keywords

  • Ran-binding protein 2 (Ranbp2)
  • Amyotrophic lateral sclerosis (ALS)
  • Microglia
  • Nucleocytoplasmic transport
  • Metalloproteinase-28 (Mmp28)
  • Acetyl-CoA carboxylase 1 (Acc1)
  • Retinal ganglion neurons