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The Role of Deimination in Regenerative Reprogramming of Neurons

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Abstract

Neurons from the adult central nervous system (CNS) demonstrate limited mRNA transport and localized protein synthesis versus developing neurons, correlating with lower regenerative capacity. We found that deimination (posttranslational conversion of protein-bound arginine into citrulline) undergoes upregulation during early neuronal development while declining to a low basal level in adults. This modification is associated with neuronal arborization from amphibians to mammals. The mRNA-binding proteins (ANP32a, REF), deiminated in neurons, have been implicated in local protein synthesis. Overexpression of the deiminating cytosolic enzyme peptidyl arginine deiminase 2 in nervous systems results in increased neuronal transport and neurite outgrowth. We further demonstrate that enriching deiminated proteins rescues transport deficiencies both in primary neurons and mouse optic nerve even in the presence of pharmacological transport blockers. We conclude that deimination promotes neuronal outgrowth via enhanced transport and local protein synthesis and represents a new avenue for neuronal regeneration in the adult CNS.

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Acknowledgments

We thank A. Trzeciecka for providing part of the neurons. We thank G. Gaidosh for assistance with microscopy. We thank Dr. K. Park for the critical comments on the manuscript.

Funding

This work was partially supported by an unrestricted grant from Research to Prevent Blindness to the University of Miami, DoD grant W81XWH-16-1-0715, and NIH grants P30 EY014801, EY014957, EY019077, NS034773, and U01EY027257.

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Authors and Affiliations

  1. Bascom Palmer Eye Institute, University of Miami, 1638 N.W. 10th Avenue, #706, Miami, FL, 33136, USA

    Di Ding, Mabel Enriquez-Algeciras, Anddre Osmar Valdivia, Juan Torres, Tsung-han Chou, Vittorio Porciatti & Sanjoy K. Bhattacharya

  2. Department of Ophthalmology/Neuroscience Program, University of Miami, Miami, FL, 33136, USA

    Di Ding, Mabel Enriquez-Algeciras, Anddre Osmar Valdivia, Juan Torres, Cameron Pole, Tsung-han Chou, Miguel Perez-Pinzon, Vittorio Porciatti & Sanjoy K. Bhattacharya

  3. Neurological Surgery, University of Miami, Miami, FL, 33136, USA

    John W Thompson

  4. Department of Neurology, University of Miami, Miami, FL, 33136, USA

    Miguel Perez-Pinzon

  5. Department of Physiology and Biophysics, State University of New York, Buffalo, 553 Biomedical Res. Building, Buffalo, NY, 14214, USA

    Susan Udin

  6. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1065, New York, NY, 10029, USA

    Eric Nestler

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  1. Di Ding
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Ding, D., Enriquez-Algeciras, M., Valdivia, A.O. et al. The Role of Deimination in Regenerative Reprogramming of Neurons. Mol Neurobiol 56, 2618–2639 (2019). https://doi.org/10.1007/s12035-018-1262-y

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