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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 2

Decreased deimination in demyelinating diseases occurs in the neurons.

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Decreased deimination in demyelinating diseases occurs in the neurons.
(...
(A) Validation of deimination in RGCs using small-molecule phenotyping (42) in mouse retina. Multispectral visualization of citrulline (red channel), GABA (green channel), and glutamate (blue channel). RPE, retinal pigmented epithelium. (B) Citrulline immunoreactivity in gray scale channel. Scale bars: 50 μm (A, B). (C) Enlargement of the boxed region (90 μm) in A. Circled cells 1–9 are RGCs with strong deimination signals. (D) Varied GABA signals. (E) Cells 4 and 8 have strong glutamate signals. (F) Cells labeled “i” (as noted in panel C) are displaced amacrine cells and have weaker citrullination (∼2-fold less). Scale bar: 15 μm (F). (G and H) Detection of presynaptic (Syntaxin-1, red) and postsynaptic (PSD 95, green) markers in control (G) and ND4 (H) retinas (arrowhead indicates region around RGCs). Scale bars: 20 μm (G and H). (I–L) Detection of deimination (using anti-citrulline [Cit]) in isolated astrocytes from control (I and K) and ND4 (J and L) mice. Panels K and L are the merged figure of GFAP (green) and deimination. (M–P) Detection of deimination (red) in isolated RGCs from control (M and O) and ND4 (N and P) mice. Panels O and P are the merged figure of Thy1 (green) and deimination. Scale bars: 20 μm (I–P). (Q and R) ELISA analyses of deimination for GFAP- (Q) and Thy1-positive cells (R) from control and ND4 mice. 10 μg of deiminated MBP (positive) and CRALBP (negative) used as controls. *P < 0.05

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ISSN: 0021-9738 (print), 1558-8238 (online)

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