Modulation of histone H3K4 dimethylation by spermidine ameliorates motor neuron survival and neuropathology in a mouse model of ALS.
Modulation of histone H3K4 dimethylation by spermidine ameliorates motor neuron survival and neuropathology in a mouse model of ALS.
复制标题
DOI：
10.1186/s12929-022-00890-3
复制
发表时间：
2022-12-20
影响因子：
11
通讯作者：
中科院分区：
文献类型：
--
作者：
肌萎缩侧索硬化症(ALS)是一种以运动神经元变性引起的进行性瘫痪为特征的致死性神经退行性疾病。已有研究表明，表观遗传修饰和转录失调可能与运动神经元死亡有关。在本研究中，我们探讨了靶向赖氨酸特异性组蛋白去甲基酶1(LSD1)的治疗方法的基础，并阐明了LSD1-组蛋白H3K4信号通路在ALS发病机制中的作用。为了研究亚精胺(SD)在ALS动物模型(G93A)中的作用，我们对ALS动物模型(G93A)进行了神经病理学分析、体重和生存评估。在此，我们发现在ALS的细胞和动物模型中，LSD1的活性增加，而LSD1的底物H3K4me2的水平降低。丹参对ALS小鼠腰髓ChAT阳性运动神经元的LSD1活性有调节作用，并能恢复H3K4me2的水平。SD通过改善ALS小鼠运动神经元的数量和大小来防止细胞损伤。SD还可减少腰髓白质和灰质GFAP阳性星形胶质细胞的生成，改善ALS小鼠的神经病理。此外，SD还能改善ALS小鼠的转杆运动能力和步态分析。最后，给药延缓了ALS(G93A)转基因小鼠的发病，延长了他们的寿命。总之，用小分子化合物调节LSD1等表观遗传靶点可能是治疗ALS的一种有用的治疗策略。网上版载有补充材料，可在10.1186/s12929-022-00890-3查阅。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to motor neuron degeneration. It has been proposed that epigenetic modification and transcriptional dysregulation may contribute to motor neuron death. In this study, we investigate the basis for therapeutic approaches to target lysine-specific histone demethylase 1 (LSD1) and elucidate the mechanistic role of LSD1-histone H3K4 signaling pathway in ALS pathogenesis. In order to examine the role of spermidine (SD), we administered SD to an animal model of ALS (G93A) and performed neuropathological analysis, body weight, and survival evaluation. Herein, we found that LSD1 activity is increased while levels of H3K4me2, a substrate of LSD1, is decreased in cellular and animal models of ALS. SD administration modulated the LSD1 activity and restored H3K4me2 levels in ChAT-positive motor neurons in the lumbar spinal cord of ALS mice. SD prevented cellular damage by improving the number and size of motor neurons in ALS mice. SD administration also reduced GFAP-positive astrogliogenesis in the white and gray matter of the lumbar spinal cord, improving the neuropathology of ALS mice. Moreover, SD administration improved the rotarod performance and gait analysis of ALS mice. Finally, SD administration delayed disease onset and prolonged the lifespan of ALS (G93A) transgenic mice. Together, modulating epigenetic targets such as LSD1 by small compounds may be a useful therapeutic strategy for treating ALS. The online version contains supplementary material available at 10.1186/s12929-022-00890-3.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
--
作者：
Cunha-Oliveira T;Montezinho L;Mendes C;Firuzi O;Saso L;Oliveira PJ;Silva FSG
通讯作者：
Silva FSG
影响因子：
3.9
作者：
Fitzpatrick PF
通讯作者：
Fitzpatrick PF
影响因子：
3.7
作者：
Heikkinen T;Bragge T;Bhattarai N;Parkkari T;Puoliväli J;Kontkanen O;Sweeney P;Park LC;Munoz-Sanjuan I
通讯作者：
Munoz-Sanjuan I
影响因子：
7.7
作者：
Hezroni, Hadas;Perry, Rotem B-T;Ulitsky, Igor
通讯作者：
Ulitsky, Igor