Mastronardi Fabrizio G, Noor Abdul, Wood D Denise, Paton Tara, Moscarello Mario A
Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada.
J Neurosci Res. 2007 Jul;85(9):2006-16. doi: 10.1002/jnr.21329.
In previous studies, we documented increased citrullinated myelin basic protein (MBP) was present in MBP isolated from multiple sclerosis (MS) normal appearing white matter (NAWM). This increase was due to the myelin enzyme peptidyl argininedeiminase 2 (PAD2). In this study, we show that methylation of cytosine of the PAD2 promoter in DNA from MS NAWM was decreased to one-third of the level of that in DNA from normal white matter. The PAD2 promoter in DNA from thymus obtained from the same MS patients and white matter DNA from Alzheimer's, Huntington's, and Parkinson's was not hypomethylated. DNA demethylase activity in supernatants prepared from NAWM of MS patients was 2-fold higher than the DNA demethylase from normal, Alzheimer's, Huntington's and Parkinson's disease white matter. The amount of PAD2 enzyme and citrullinated MBP was increased in MS NAWM. The decreased methylation of cytosines in the PAD2 promoter may explain the increased synthesis of PAD2 protein that is responsible for the increased amount of citrullinated MBP, which in turn results in loss of myelin stability in MS brain.
在先前的研究中，我们记录到从多发性硬化症（MS）患者正常外观白质（NAWM）中分离出的髓鞘碱性蛋白（MBP）中，瓜氨酸化的MBP有所增加。这种增加是由髓鞘酶肽基精氨酸脱亚氨酶2（PAD2）引起的。在本研究中，我们发现MS患者NAWM的DNA中，PAD2启动子的胞嘧啶甲基化水平降至正常白质DNA的三分之一。来自同一MS患者胸腺的DNA以及来自阿尔茨海默病、亨廷顿病和帕金森病患者白质DNA中的PAD2启动子并未发生低甲基化。MS患者NAWM制备的上清液中的DNA去甲基酶活性比正常、阿尔茨海默病、亨廷顿病和帕金森病患者白质中的DNA去甲基酶活性高2倍。MS患者NAWM中PAD2酶和瓜氨酸化MBP的量增加。PAD2启动子中胞嘧啶甲基化的降低可能解释了PAD2蛋白合成增加的原因，而PAD2蛋白合成增加导致瓜氨酸化MBP量增加，进而导致MS患者大脑中髓鞘稳定性丧失。
