de Boni Laura, Riedel Linda, Schmitt Ina, Kraus Theo F J, Kaut Oliver, Piston Dominik, Akbarian Schahram, Wüllner Ullrich
Department of Neurology, University Clinic, University of Bonn, Bonn, Germany.
Department of Neurology, German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Bonn, Germany.
Neurobiol Aging. 2015 Dec;36(12):3334.e7-3334.e11. doi: 10.1016/j.neurobiolaging.2015.08.028. Epub 2015 Sep 8.
DNA methylation patterns change with age, and aging itself is a major confounding risk factor for Parkinson's disease (PD). Duplication and triplication, that is, increased expression of the α-synuclein (SNCA) gene, cause familial PD, and demethylation of SNCA intron 1 has been shown to result in increased expression of SNCA. We thus hypothesized that age-related alterations of SNCA methylation might underly the increased susceptibility toward PD in later life. The present study sought to determine (1) whether alterations of SNCA intron 1 methylation occurred during aging, (2) whether the methylation pattern differed between men and women, and (3) whether purified neurons compared with non-neuronal cells exhibited different methylation patterns. The analysis of DNA from brain tissue and fluorescence activated cell sorting-sorted purified neurons of 41 individuals revealed only a minor increase of SNCA intron 1 DNA methylation levels in presumably healthy individuals during aging but no significant difference between men and women. Interestingly enough, methylation of SNCA intron 1 was higher in neurons compared with non-neuronal cells, although non-neuronal cells express lower levels of SNCA. Therefore, the normal pattern of SNCA methylation during aging should not result in increased expression of α-synuclein protein. It is thus likely that additional, yet not identified, mechanisms contribute to the tissue specificity of SNCA expression and the presumed dysregulation in PD.
DNA甲基化模式随年龄变化，而衰老本身是帕金森病（PD）的一个主要混杂风险因素。α-突触核蛋白（SNCA）基因的重复和三倍体化，即该基因表达增加，会导致家族性PD，并且已证明SNCA内含子1的去甲基化会导致SNCA表达增加。因此，我们推测SNCA甲基化的年龄相关变化可能是晚年对PD易感性增加的基础。本研究旨在确定：（1）衰老过程中SNCA内含子1甲基化是否发生改变；（2）男性和女性的甲基化模式是否不同；（3）与非神经元细胞相比，纯化的神经元是否表现出不同的甲基化模式。对41名个体的脑组织DNA以及荧光激活细胞分选技术分选的纯化神经元进行分析后发现，在可能健康的个体衰老过程中，SNCA内含子1的DNA甲基化水平仅略有增加，但男性和女性之间没有显著差异。有趣的是，与非神经元细胞相比，神经元中SNCA内含子1的甲基化水平更高，尽管非神经元细胞中SNCA的表达水平较低。因此，衰老过程中SNCA甲基化的正常模式不应导致α-突触核蛋白的表达增加。因此，可能还有其他尚未确定的机制导致了SNCA表达的组织特异性以及PD中推测的失调。
