LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

被引：20

作者：

Baba, Rina ^{[1
]}

Matsuda, Satoru ^{[1
]}

Arakawa, Yuuichi ^{[1
,4
]}

Yamada, Ryuji ^{[1
]}

Suzuki, Noriko ^{[1
,4
]}

Ando, Tatsuya ^{[2
]}

Oki, Hideyuki ^{[3
,4
]}

Igaki, Shigeru ^{[3
]}

Daini, Masaki ^{[1
]}

Hattori, Yasushi ^{[1
]}

Matsumoto, Shigemitsu ^{[1
,5
]}

Ito, Mitsuhiro ^{[1
,4
]}

Nakatani, Atsushi ^{[1
]}

Kimura, Haruhide ^{[1
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Neurosci Drug Discovery Unit, Res, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan

[2] Takeda Pharmaceut Co Ltd, Res, Computat Biol, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan

[3] Takeda Pharmaceut Co Ltd, Res, Biomol Res Labs, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan

[4] Axcelead Drug Discovery Partners Inc, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2510012, Japan

[5] SCOHIA PHARMA Inc, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan

来源：

SCIENCE ADVANCES | 2021年 / 7卷 / 11期

关键词：

IMMUNE ACTIVATION; DEMETHYLASE; METHYLATION; EXPOSURE;

D O I：

10.1126/sciadv.aba1187

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

引用

页数：15

共 1 条

[1] Investigating the Therapeutic Potential of LSD1 Enzyme Activity-Specific Inhibition by TAK-418 for Social and Memory Deficits in Rodent Disease Models
Baba, Rina
Matsuda, Satoru
Maeda, Ryota
Murakami, Koji
Yamamoto, Yukiko
Nakatani, Atsushi
Kimura, Haruhide
ACS CHEMICAL NEUROSCIENCE, 2022, 13 (03): : 313 - 321

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