Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Institute for Biological Psychiatry, Mental Health Centre Sct. Hans, Roskilde, Denmark.
PLoS Genet. 2018 Dec 19;14(12):e1007623. doi: 10.1371/journal.pgen.1007623. eCollection 2018 Dec.
The human 1q21.1 deletion of ten genes is associated with increased risk of schizophrenia. This deletion involves the β-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell. Although neurons have a high demand for energy and low capacity to store nutrients, the role of AMPK in neuronal physiology is poorly defined. Here we show that AMPK is important in the nervous system for maintaining neuronal integrity and for stress survival and longevity in Drosophila. To understand the impact of this signaling system on behavior and its potential contribution to the 1q21.1 deletion syndrome, we focused on sleep, an important role of which is proposed to be the reestablishment of neuronal energy levels that are diminished during energy-demanding wakefulness. Sleep disturbances are one of the most common problems affecting individuals with psychiatric disorders. We show that AMPK is required for maintenance of proper sleep architecture and for sleep recovery following sleep deprivation. Neuronal AMPKβ loss specifically leads to sleep fragmentation and causes dysregulation of genes believed to play a role in sleep homeostasis. Our data also suggest that AMPKβ loss may contribute to the increased risk of developing mental disorders and sleep disturbances associated with the human 1q21.1 deletion.
人类 1q21.1 缺失十个基因与精神分裂症风险增加有关。该缺失涉及 AMP 激活蛋白激酶（AMPK）复合物的β亚基，这是细胞中的一个关键能量传感器。尽管神经元对能量的需求很高，储存营养物质的能力很低，但 AMPK 在神经元生理学中的作用还未明确界定。本文中，我们证明了 AMPK 在维持神经元完整性以及果蝇的应激生存和寿命方面在神经系统中具有重要作用。为了了解该信号系统对行为的影响及其对 1q21.1 缺失综合征的潜在贡献，我们将重点放在睡眠上，睡眠的一个重要作用是重建在需要能量的清醒期间减少的神经元能量水平。睡眠障碍是影响精神疾病患者的最常见问题之一。我们证明了 AMPK 对于维持适当的睡眠结构和睡眠剥夺后的睡眠恢复是必需的。神经元 AMPKβ 的丧失会导致睡眠碎片化，并导致被认为在睡眠稳态中发挥作用的基因失调。我们的数据还表明，AMPKβ 的丧失可能导致与人类 1q21.1 缺失相关的精神障碍和睡眠障碍风险增加。
