Retinal restoration
Demyelinating diseases, such as multiple sclerosis (MS), are frequently associated with the progressive loss of vision. The retinal nerve damage is thought to be caused by immune system-mediated inflammation; however, other demyelinating disorders, such as Pelizaeus-Merzbacher disease, do not involve the immune system, suggesting that there are other causes of retinal nerve damage. Deimination is a protein modification that is altered in patients with MS and PMD. Enriquez-Algeciras et al. investigated the role of deimination in retinal nerve damage in a mouse model of demyelinating disease (ND4 mice). The image above shows immunohistochemistry in an ND4 mouse retina, with citrulline (red), GABA (green), and glutamate (blue). Enriquez-Algeciras and colleagues found that deimination was reduced in patients with demyelinating diseases and in ND4 mice that exhibited vision loss. Decreases in deimination could be detected in the mice prior to the onset of other symptoms. Restoration of deimination improved visual function in ND4 mice. These results demonstrate that loss of deimination underlies nerve damage in demyelinating diseases and may be a suitable target for therapeutic intervention.
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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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ISSN: 0021-9738 (print), 1558-8238 (online)