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

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

doi:10.1371/journal.pgen.1007623

Cited by 32 publications

(19 citation statements)

References 70 publications

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“…We found that the genes associated with the top 30% SNPs were significantly enriched in eight pathways involved in regulating nervous system functions. For example, Axon guidance and AMPK signaling pathways identified in this work were proved to be linked to SCZ and bipolar BPD [15].…”

Section: Introductionmentioning

confidence: 74%

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Manifold Learning Analysis for Allele-Skewed DNA Modification SNPs for Psychiatric Disorders

Liu

Han

2020

IEEE Access

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Bipolar disorder (BPD) and schizophrenia (SCZ) are two severe worldwide psychiatric disorders. Identifying genetic components contributing to both disorders will provide meaningful insights into their pathogenesis and widely-existed misdiagnosis. In this study, we employ allele-skewed DNA modification (ASM-SNP) data to investigate the two psychiatric disorders via state-of-the-art manifold learning, data-driven feature selection, and novel pathway analysis. We propose a novel manifold learning analysis for ASM-SNP data of bipolar disorder and schizophrenia based on a data-driven feature selection algorithm: nonnegative singular value approximation (NSVA). Our results indicate that t-distributed stochastic neighbor embedding (t-SNE) outperforms its peers in distinguishing psychiatric disorder samples from normal ones in both visualization and phenotype classification. It achieves the best phenotype diagnosis results with the average AUC 0.95 by using only about 20% top-ranked SNPs. Furthermore, our results from manifold learning along with support vector machine analysis suggest that the possible non-separability of SCZ and BPD in genetics. We also validate that SCZ and BPD both share the same or similar genetic variations from pathway analysis. This study indicates the inevitable misdiagnosis issue between BPD and SCZ from a machine learning and systems biology approach. The result sheds light on the existing psychiatry research to reexamine the existing behavior-based classification for BPD and SCZ. To the best of our knowledge, this study is the first comprehensive investigation of BPD and SCZ in bioinformatics.

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Section: Introductionmentioning

confidence: 74%

“…Besides, the nicotine addiction and AMPK signaling pathways were found to be related to the activity of neurotransmitters in the brain [15], [69]. People with a symptom of severe depression, schizophrenia, or bipolar disorder commonly had signs of a circadian entrainment disorder [70].…”

Section: G Snp Driven Pathway Enrichment Analysismentioning

confidence: 99%

Manifold Learning Analysis for Allele-Skewed DNA Modification SNPs for Psychiatric Disorders

Liu

Han

2020

IEEE Access

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“…Drosophila sleep has been rigorously examined and found to exhibit several of the mammalian hallmarks of sleep, such as sustained periods of quiescence, increased arousal threshold, and circadian and homeostatic regulation [13,14]. Indeed, recent studies in Drosophila have identified genes associated with human neurodevelopmental and psychiatric disorders that disrupt sleep and circadian rhythm, such as the candidate autism-spectrum-disorder gene Cullin-3 (Cul3) [15,16] and the gene alicorn (alc) linked to the 1q21.1 deletion, another deletion that confers schizophrenia risk [17].…”

Section: Introductionmentioning

confidence: 99%

Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

et al. 2020

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The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of known genes, the contribution of each of these to the 22q11.2 deletion syndrome (DS) is not known. To investigate the effect of individual genes within this interval on the pathophysiology associated with the deletion, we analyzed their role in sleep, a behavior affected in virtually all psychiatric disorders, including the 22q11.2 DS. We identified the gene LZTR1 (night owl, nowl) as a regulator of night-time sleep in Drosophila. In humans, LZTR1 has been associated with Rasdependent neurological diseases also caused by Neurofibromin-1 (Nf1) deficiency. We show that Nf1 loss leads to a night-time sleep phenotype nearly identical to that of nowl loss and that nowl negatively regulates Ras and interacts with Nf1 in sleep regulation. Furthermore, nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep phenotype, and this defect can be rescued by increased GABA A receptor signaling, indicating that Nowl regulates sleep through modulation of GABA signaling. Our results suggest that nowl/LZTR1 may be a conserved regulator of GABA signaling important for normal sleep that contributes to the 22q11.2 DS.

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“…It is interesting to speculate that this mechanism might also contribute during sleep, when breathing slows and central energy reserves are replenished. Indeed, knockdown of AMPK in the central nervous system of the fruit fly Drosophila melanogaster led to disturbances in sleep patterns and to poorer recovery from sleep deprivation [101].…”

Section: Ampk and Central Neural Control Mechanismsmentioning

confidence: 99%

AMPK and the Need to Breathe and Feed: What’s the Matter with Oxygen?

Evans

Hardie

2020

IJMS

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We live and to do so we must breathe and eat, so are we a combination of what we eat and breathe? Here, we will consider this question, and the role in this respect of the AMP-activated protein kinase (AMPK). Emerging evidence suggests that AMPK facilitates central and peripheral reflexes that coordinate breathing and oxygen supply, and contributes to the central regulation of feeding and food choice. We propose, therefore, that oxygen supply to the body is aligned with not only the quantity we eat, but also nutrient-based diet selection, and that the cell-specific expression pattern of AMPK subunit isoforms is critical to appropriate system alignment in this respect. Currently available information on how oxygen supply may be aligned with feeding and food choice, or vice versa, through our motivation to breathe and select particular nutrients is sparse, fragmented and lacks any integrated understanding. By addressing this, we aim to provide the foundations for a clinical perspective that reveals untapped potential, by highlighting how aberrant cell-specific changes in the expression of AMPK subunit isoforms could give rise, in part, to known associations between metabolic disease, such as obesity and type 2 diabetes, sleep-disordered breathing, pulmonary hypertension and acute respiratory distress syndrome.

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

Cited by 32 publications

References 70 publications

Manifold Learning Analysis for Allele-Skewed DNA Modification SNPs for Psychiatric Disorders

Manifold Learning Analysis for Allele-Skewed DNA Modification SNPs for Psychiatric Disorders

Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

AMPK and the Need to Breathe and Feed: What’s the Matter with Oxygen?

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