Hartung T, Rhein M, Kalmbach N, Thau-Habermann N, Naujock M, Müschen L, Frieling H, Sterneckert J, Hermann A, Wegner F, Petri S
Department of Neurology, Hannover Medical School, Hannover, Germany.
Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Front Cell Dev Biol. 2021 Nov 19;9:774751. doi: 10.3389/fcell.2021.774751. eCollection 2021.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease leading to degeneration of motor neurons (MNs). Epigenetic modification of gene expression is increasingly recognized as potential disease mechanism. In the present study we generated motor neurons from induced pluripotent stem cells from ALS patients carrying a mutation in the fused in sarcoma gene (FUS) and analyzed expression and promoter methylation of the FUS gene and expression of DNA methyltransferases () compared to healthy control cell lines. While mutant neural progenitor cells (NPCs) did not show a difference in and expression compared to healthy controls, differentiated mutant motor neurons showed significantly lower expression, higher expression and higher methylation of the proximal gene promoter. Immunofluorescence revealed perceived proximity of cytoplasmic aggregates in ALS MNs together with 5-methylcytosin (5-mC). Targeting disturbed methylation in ALS may therefore restore transcriptional alterations and represent a novel therapeutic strategy.
肌萎缩侧索硬化症（ALS）是一种导致运动神经元（MNs）退化的快速进展性疾病。基因表达的表观遗传修饰日益被认为是潜在的疾病机制。在本研究中，我们从携带肉瘤融合基因（FUS）突变的ALS患者的诱导多能干细胞中生成运动神经元，并与健康对照细胞系相比，分析了FUS基因的表达和启动子甲基化以及DNA甲基转移酶的表达。虽然与健康对照相比，突变神经祖细胞（NPCs）在和表达上没有差异，但分化的突变运动神经元显示出明显较低的表达、较高的表达以及近端基因启动子的较高甲基化。免疫荧光显示ALS运动神经元中细胞质聚集体与5-甲基胞嘧啶（5-mC）之间存在明显的接近度。因此，针对ALS中受干扰的甲基化可能恢复转录改变，并代表一种新的治疗策略。
