Disrupted-in-schizophrenia 1 enhances the quality of circadian rhythm by stabilizing BMAL1

Su Been Lee, Jihyun Park, Yongdo Kwak, Young Un Park, Truong Thi My Nhung, Bo Kyoung Suh, Youngsik Woo, Yeongjun Suh, Eunbyul Cho, Sehyung Cho, Sang Ki Park

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that has been implicated in multiple mental disorders. DISC1 is known to regulate neuronal proliferation, signaling, and intracellular calcium homeostasis, as well as neurodevelopment. Although DISC1 was linked to sleep-associated behaviors, whether DISC1 functions in the circadian rhythm has not been determined yet. In this work, we revealed that Disc1 expression exhibits daily oscillating pattern and is regulated by binding of circadian locomotor output cycles kaput (CLOCK) and Brain and muscle Arnt-like protein-1 (BMAL1) heterodimer to E-box sequences in its promoter. Interestingly, Disc1 deficiency increases the ubiquitination of BMAL1 and de-stabilizes it, thereby reducing its protein levels. DISC1 inhibits the activity of GSK3β, which promotes BMAL1 ubiquitination, suggesting that DISC1 regulates BMAL1 stability by inhibiting its ubiquitination. Moreover, Disc1-deficient cells and mice show reduced expression of other circadian genes. Finally, Disc1-LI (Disc1 knockout) mice exhibit damped circadian physiology and behaviors. Collectively, these findings demonstrate that the oscillation of DISC1 expression is under the control of CLOCK and BMAL1, and that DISC1 contributes to the core circadian system by regulating BMAL1 stability.

Original languageEnglish
Article number110
JournalTranslational Psychiatry
Volume11
Issue number1
DOIs
Publication statusPublished - Jun 2021

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