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

Publication ,  Journal Article
Cho, K-I; Yoon, D; Yu, M; Peachey, NS; Ferreira, PA
Published in: Cell Mol Life Sci
September 2019

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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Published In

Cell Mol Life Sci

DOI

EISSN

1420-9071

Publication Date

September 2019

Volume

76

Issue

17

Start / End Page

3407 / 3432

Location

Switzerland

Related Subject Headings

  • Transcriptome
  • Thy-1 Antigens
  • Tamoxifen
  • Retinal Ganglion Cells
  • Paracrine Communication
  • Optic Nerve
  • Nuclear Pore Complex Proteins
  • Motor Neurons
  • Molecular Chaperones
  • Microglia
 

Citation

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Cho, K.-I., Yoon, D., Yu, M., Peachey, N. S., & Ferreira, P. A. (2019). 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(17), 3407–3432. https://doi.org/10.1007/s00018-019-03078-5
Cho, Kyoung-In, Dosuk Yoon, Minzhong Yu, Neal S. Peachey, and Paulo A. Ferreira. “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, no. 17 (September 2019): 3407–32. https://doi.org/10.1007/s00018-019-03078-5.
Cho, Kyoung-In, 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, vol. 76, no. 17, Sept. 2019, pp. 3407–32. Pubmed, doi:10.1007/s00018-019-03078-5.
Journal cover image

Published In

Cell Mol Life Sci

DOI

EISSN

1420-9071

Publication Date

September 2019

Volume

76

Issue

17

Start / End Page

3407 / 3432

Location

Switzerland

Related Subject Headings

  • Transcriptome
  • Thy-1 Antigens
  • Tamoxifen
  • Retinal Ganglion Cells
  • Paracrine Communication
  • Optic Nerve
  • Nuclear Pore Complex Proteins
  • Motor Neurons
  • Molecular Chaperones
  • Microglia