Deimination restores inner retinal visual function in murine demyelinating disease
Mabel Enriquez-Algeciras, … , Vittorio Porciatti, Sanjoy K. Bhattacharya
Mabel Enriquez-Algeciras, … , Vittorio Porciatti, Sanjoy K. Bhattacharya
Published January 2, 2013
Citation Information: J Clin Invest. 2013;123(2):646-656. https://doi.org/10.1172/JCI64811.
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Deimination restores inner retinal visual function in murine demyelinating disease

Abstract

Progressive loss of visual function frequently accompanies demyelinating diseases such as multiple sclerosis (MS) and is hypothesized to be the result of damage to the axons and soma of neurons. Here, we show that dendritic impairment is also involved in these diseases. Deimination, a posttranslational modification, was reduced in the retinal ganglion cell layer of MS patients and in a transgenic mouse model of MS (ND4 mice). Reduced deimination accompanied a decrease in inner retinal function in ND4 mice, indicating loss of vision. Local restoration of deimination dramatically improved retinal function and elongation of neurites in isolated neurons. Further, neurite length was decreased by downregulation of deimination or siRNA knockdown of the export-binding protein REF, a primary target for deimination in these cells. REF localized to dendrites and bound selective mRNAs and translation machinery to promote protein synthesis. Thus, protein deimination and dendritic outgrowth play key roles in visual function and may be a general feature of demyelinating diseases.

Authors

Mabel Enriquez-Algeciras, Di Ding, Fabrizio G. Mastronardi, Robert E. Marc, Vittorio Porciatti, Sanjoy K. Bhattacharya

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Figure 1

Relative hypodeimination in the RGC layer in demyelinating diseases.

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Relative hypodeimination in the RGC layer in demyelinating diseases. (A–...
(A–M) Immunofluorescence analyses to determine deimination levels. (A and B) Representative normal and MS brains (cerebral cortex; each from a 76-year-old male of mixed European descent) subjected to monoxime treatment, using an anti–citrulline-monoxime adduct antibody (green); (C and D) representative normal and MS human retinas treated as in A. Thin and thick arrows indicate normal and hyperdeimination, respectively. Scale bars: 100 μm (A–D). (E) Retinal sections from normal 5-month-old control mice and (F) transgenic ND4 mice treated as in A. Yellow thin arrows (E) indicate a subset of RGCs that is deiminated (green). Fluorescent spots (box and inset) are absent in ND4 mice (F). (G and H) Controls without monoxime treatment subjected to anti–citrulline-monoxime adduct immunofluorescence. Blue arrows (F) indicate hyperdeiminated regions. Arrowheads show nuclei stained with DAPI (blue). GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PR, photoreceptor layer. Scale bars: 50 μm; 15 μm (inset) (E–H). (I and J) Sections of control (CD1) and ND4 mice brain (5 month old) treated as in A. (K) Citrullinated RGC numbers in 0.1 sq. mm of human retina from 5 control and 5 MS eyes (3 regions for each eye). (L) Thy1 and MAP 2 marker intensity in equal areas in GCL in control and ND4 mouse at 5 months of age. (M) The anti-citrulline–positive to Thy1-positive RGC cell ratio in the retina at indicated ages of ND4 and control mice (3 animals each) from equivalent regions of retina. *P < 0.05.