Ding D, Enriquez-Algeciras M, Dave KR, Perez-Pinzon M, Bhattacharya SK. The role of deimination in ATP5b mRNA transport in a transgenic mouse model of multiple sclerosis.EMBO Rep. 2012 Jan doi: 10.1038/embor.2011.264. [Epub ahead of print]
Deimination refers to conversion of protein-bound arginine into citrulline as a post-translational modification after DNA, is transcribed to form RNA and translated into the production of proteins. An mRNA carrier, RNA binding export factor (REF), present on mitochondria undergoes loss of deimination with impaired ATP5b mRNA transport in ND4
mice (model of multiple sclerosis) compared with the controls. We present evidence of (1) reduced ATP5b mRNA binding strength of non-deiminated REF compared with deiminated REF, (2) impaired ATP5b mRNA transport in ND4 mice and (3) reduced mitochondrial ATP synthase activity on inhibition of deimination in PC12 cells. Impaired deimination of REF and defect in mitochondrial mRNA transport are critical factors in mitochondrial dysfunction in ND4 mice.
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 (fat solubility) of the protein, leading to changes in protein folding (gives 3D structure). Myelin basic protein is citrulated as are other proteins.
ND4 mice contain 70 copies (normally it would be two copies of genes, one from your mum and one from your dad) of the transgene encoding DM20, a myelin proteolipid protein. They appear clinically normal up to 3 months of age. By 8-10 months, they show tremors, unsteady gait, and die shortly thereafter. This is associated with the development of demyelination.
This study shows that mRNA carrier, RNA binding export factor (REF), present on mitochondria undergoes loss of deimination in ND4 mice. This leads to loss of energy supply to the mitochondria (the powerhouses of cells) in nerve cells. As we have reported previously loss of energy supply in nerves that have been demyelinated can lead to progressive nerve loss. Therefore, it will be of interest to determine whether this process occurs in mutliple sclerosis as there is increasing evidence for a failure of mitochondrial function in the pathogenesis of MS.
When you know the cause you are nearer to a cure of the problem