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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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Research Article Autoimmunity

Deimination restores inner retinal visual function in murine demyelinating disease

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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 3

Restoration of deimination and visual function.

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Restoration of deimination and visual function.
(A) Evaluation of FERG a...
(A) Evaluation of FERG and PERG amplitudes in ND4 mice. Representative mean ± SD at indicated ages (n = 10 mice per group). (B–D) evaluation of visual function after PAD2 overexpression in RGCs. Representative PERG signal from an ND4 mouse at 3.5 months before injection (B) and 15 days after injection (C). Left eye: PAD2-expressing; right eye: GFP control. (D) PERG amplitude normalized to baseline for PAD2-expressing and control GFP-expressing (sham) animals for 7 injected mice at 15 days (white bars) and at 30 days (black bars). (E) Isolated RGCs from ND4 mice and (F) RGCs from ND4 mice were transfected with PAD2 lentiviral construct and incubated for identical periods. The cells were probed with anti-Thy1, anti-REF, and anti-citrulline as indicated. Scale bars: 10 μm. Arrow indicates neurite outgrowth. (G) The effects of upregulation of PAD2 on neurite outgrowth in cultured RGCs from ND4 mice, control, and PAD2-transfected neurite length measurements are as indicated. (H) Neurite length in cultured RGCs from CD1 mice upon treatment with control siRNA or siRNA against PAD2 and PAD4. In G and H, mean ± SD from 3 independent measurements (derived from 3 different animals) are shown; neurite length (μm) in each experiment was average from 40 neurons. ANOVA showed a statistically significant difference between the control and treated groups. Scheffe’s post hoc test showed that controls were statistically different from treated groups (*P < 0.005).

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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