Choi, Seung-Hye Yousefian-Jazi, Ali Hyeon, Seung Jae Nguyen, Phuong Thi Thanh Chu, Jiyeon Kim, Sojung Kim, Suhyun Ryu, Hannah L. Kowall, Neil W. Ryu, Hoon Lee, Junghee 2024-01-19T10:32:27Z 2024-01-19T10:32:27Z 2023-01-13 2022-12 1021-7770 https://pubs.kist.re.kr/handle/201004/114214 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. English S. Karger AG Modulation of histone H3K4 dimethylation by spermidine ameliorates motor neuron survival and neuropathology in a mouse model of ALS Article 10.1186/s12929-022-00890-3 1 Journal of Biomedical Science, v.29, no.1 Journal of Biomedical Science 29 1 Y scie scopus 000900970900001 2-s2.0-85144319769 Cell Biology Medicine, Research & Experimental Cell Biology Research & Experimental Medicine Article OXIDATIVE STRESS PROLONGS SURVIVAL DEMETHYLASE LSD1 ASTROCYTES MUTANT GLUTAMATE ARGININE GENE INHIBITION Amyotrophic lateral sclerosis LSD1 Spermidine Motor neuron