AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance

Stanislav Nagy; Gianna W Maurer; Julie L Hentze; Morten Rose; Thomas M Werge; Kim Rewitz

doi:10.1371/journal.pgen.1007623

AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance

PLoS Genet. 2018 Dec 19;14(12):e1007623. doi: 10.1371/journal.pgen.1007623. eCollection 2018 Dec.

Authors

Stanislav Nagy¹, Gianna W Maurer¹, Julie L Hentze^{1

2

3}, Morten Rose¹, Thomas M Werge², Kim Rewitz¹

Affiliations

¹ Department of Biology, University of Copenhagen, Copenhagen, Denmark.
² Institute for Biological Psychiatry, Mental Health Centre Sct. Hans, Roskilde, Denmark.
³ Department of Pathology, Herlev Hospital, Herlev, Denmark.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / antagonists & inhibitors
AMP-Activated Protein Kinases / deficiency
AMP-Activated Protein Kinases / genetics*
Abnormalities, Multiple / enzymology*
Abnormalities, Multiple / genetics*
Animals
Chromosome Deletion
Chromosomes, Human, Pair 1 / enzymology
Chromosomes, Human, Pair 1 / genetics
Drosophila Proteins / deficiency
Drosophila Proteins / genetics
Drosophila melanogaster / enzymology
Drosophila melanogaster / genetics
Female
Gene Knockdown Techniques
Genetic Predisposition to Disease
Humans
Learning / physiology
Longevity / genetics
Longevity / physiology
Male
Megalencephaly / enzymology*
Megalencephaly / genetics*
Models, Animal
Neurons / cytology
Neurons / enzymology*
Risk Factors
Schizophrenia / enzymology*
Schizophrenia / genetics*
Signal Transduction
Sleep / genetics*
Sleep / physiology*
Sleep Wake Disorders / enzymology
Sleep Wake Disorders / genetics

Substances

Drosophila Proteins
PRKAB2 protein, human
AMP-Activated Protein Kinases

Supplementary concepts

Chromosome 1q21.1 Deletion Syndrome, 1.35-Mb

Grants and funding

This work was supported by the Danish Council for Independent Research, Medical Sciences grant 4183-00312 to KR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.