- 作者: Seung-Hye Choi, Ali Yousefian-Jazi, Seung Jae Hyeon, Phuong Thi Thanh Nguyen, Jiyeon Chu, Sojung Kim, Suhyun Kim, Hannah L. Ryu, Neil W. Kowall, Hoon Ryu & Junghee Lee
- 作者服務機構: 1.Department of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University School of Medicine, Boston, MA, 02118, USA 2.Integrated Biomedical and Life Science Department, Graduate School, Korea University, Seoul, 02841, South Korea 3.KIST School, Division of Bio-Medical Science & Technology, University of Science and Technology (UST), Seoul, 02792, South Korea 4.K-Laboratory, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, South Korea 5.VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA, 02130, USA
- 中文摘要:
- 英文摘要:
Background
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.
Methods
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.
Results
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.
Conclusion
Together, modulating epigenetic targets such as LSD1 by small compounds may be a useful therapeutic strategy for treating ALS. - 中文關鍵字:
- 英文關鍵字: Amyotrophic lateral sclerosis, LSD1, Spermidine, Histone H3K4 dimethylation, Motor neuron