Page 82 - Q. Neuroscience

[Q. Neuroscience-50]

Modulation of histone H3K4 dimethylation by polyamine

improves neuropathology and motor neuron survival in

mouse model of ALS

Ali Yousefian-Jazi¹, Jong-Il Kim¹, Neil Kowall¹, Hoon Ryu¹, Junghee Lee¹

¹Center for Neuroscience, Korea Institute of Science and Technology, Seoul 04535, South Korea, ²Genome

Medicine Institute and Department of Biochemistry, Seoul National University, Seoul 110799, South Korea,
³Neuroscience, VA Boston Healthcare System, Boston 02130, USA, ⁴Department of Neurology, Boston University ,

Boston 02118 , USA

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. Herein, we found that the level of dimethylated histone H3K4 (H3K4me2)
is decreased in cellular and animal models of ALS, and is correlated with motor neuronal dysfunction in mutant

SOD1 (G93A) ALS mice. Spermidine administration modulated the LSD1 activity and increased H3K4me2 motor
neurons in mSOD1 (G93A) mice. Spermidine prevented neuronal damage by improving the number and size of

motor neurons in the lumbar spinal cord of mSOD1 (G93A) mice. Moreover, spermidine administration delayed the
disease onset and prolonged the lifespan of mSOD1 (G93A) transgenic ALS mice. Taken together, spermidine

modulates LSD1 activity and H3K4me2 level, and prevents the loss of motor neurons, extending the survival of ALS
mice. Modulation of epigenetic target such as LSD1 by small compounds may be a useful therapeutic strategy for

treating ALS.