Friday, 4 January 2013

Research: Epigenetics influence visual function

Deimination restores inner retinal visual function in murine demyelinating disease. Enriquez-Algeciras M, Ding D, Mastronardi FG, Marc RE, Porciatti V, Bhattacharya SK. J Clin Invest. 2013 Jan. doi:pii: 64811. 10.1172/JCI64811. [Epub ahead of print]

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 post-translational modification, was reduced in the retinal ganglion cell layer of MS patients and in a transgenic mouse model of MS (ND4). 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.
Citrullination or deimination is the term used for the post-translational modification of the amino acid arginine in a protein into the amino acid citrulline. This reaction, shown below, is performed by enzymes called peptidylarginine deiminases (PADs). The conversion of arginine into citrulline can have important consequences for the structure and function of proteins, since arginine is positively charged at a neutral pH, whereas citrulline is uncharged. This increases the hydrophobicity of the protein, leading to changes in protein folding.



The chemical conversion of arginine to citrulline, known as citrullination or deimination.

This study takes the ND4 mouse, which is a transgenic mouse harboring multiple copies of the myelin proteolipid protein (PLP), which develops dysmyelination. They found a decrease in the amount of citrulination in the retinal and this correlated with worse visual function and the local increase in this restored visual function and promoted nerve contacts. This nerve contact could be further enhanced by blockage of a protein called REF that are RNA and mRNA (the bit between DNA and amino acids and protein formation) exporting factors which are though to be involved in citrulination. This may influence synaptic plasticity that aloows MSers to compensate for the consequences of MS. 

This a form of epigenetics and citrulination in different parts of the nervous system may have different consequences

Koch MW, Metz LM, Kovalchuk O Epigenetic changes in patients with multiple sclerosis. Nat Rev Neurol. 2012 ;9:35-43

Moscarello MA, Lei H, Mastronardi FG, Winer S, Tsui H, Li Z, Ackerley C, Zhang L, Raijmakers R, Wood DD. Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis. Dis Model Mech. 2012 Nov. [Epub ahead of print]


De Ceuleneer M, Van Steendam K, Dhaenens M, Deforce D In vivo relevance of citrullinated proteins and the challenges in their detection. Proteomics. 2012;12:752-60.

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