한빛사논문
- 조회432
Seung‑Hye Choi1† , Ali Yousefian‑Jazi1† , Seung Jae Hyeon1 , Phuong Thi Thanh Nguyen1,2 , Jiyeon Chu1,3 , Sojung Kim1 , Suhyun Kim1 , Hannah L. Ryu4 , Neil W. Kowall4,5 , Hoon Ryu 1,2* and Junghee Lee4,5*
1 K‑Laboratory, Brain Science Institute, Korea Institute of Science and Technol‑ ogy (KIST), Seoul 02792, South Korea.
2 KIST School, Division of Bio‑Medical Sci‑ ence & Technology, University of Science and Technology (UST), Seoul 02792, South Korea.
3 Integrated Biomedical and Life Science Department, Graduate School, Korea University, Seoul 02841, South Korea.
4 Department of Neurol‑ ogy, Boston University Alzheimer’s Disease Research Center, Boston University School of Medicine, Boston, MA 02118, USA.
5 VA Boston Healthcare System, 150 S. Huntington Avenue, Boston, MA 02130, USA.
† Seung‑Hye Choi and Ali Yousefian‑Jazi contributed equally to this work
*Correspondence: Hoon Ryu, Junghee Lee
Abstract
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.
논문정보
- Research article
- 2022년 12월 (BRIC 등록일 2022-12-28)
- 국내(교신)+국외 연구진
- 의약학 > 신경의학
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