Exploration of sleep in a fly model related to schizophrenia

Nagy S, Maurer GW, Hentze JL, Rose M, Werge TM, Rewitz K. 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. PMID: 30566533; PMCID: PMC6317821.

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."

Aggression among flies as a model behavior for studies related to human neurological disorders

Zwarts L, Vulsteke V, Buhl E, Hodge JJ, Callaerts P. SlgA, the homologue of the human schizophrenia associated PRODH gene, acts in clock neurons to regulate Drosophila aggression. Dis Model Mech. 2017 Mar 22. pii: dmm.027151. PMID: 28331058.

From the abstract: "Mutations in proline dehydrogenase (PRODH) are linked to behavioral alterations in schizophrenia ... We here establish a Drosophila model to study the role of PRODH in behavioral disorders. We ... show that knock-down and overexpression of human PRODH and slgA in the lateral neurons ventral (LNv) lead to altered aggressive behavior. SlgA acts in an isoform-specific manner and is regulated by casein kinase II (CkII). Our data suggest that these effects are, at least partially, due to effects on mitochondrial function. We thus show that precise regulation of proline metabolism is essential to drive normal behavior and we identify Drosophila aggression as a model behavior relevant for the study of mechanisms impaired in neuropsychiatric disorders."

Drosophila studies contribute to research on possible links between the metal copper and schizophrenia

Gokhale A, Vrailas-Mortimer A, Larimore J, Comstra HS, Zlatic SA, Werner E, Manvich DF, Iuvone PM, Weinshenker D, Faundez V. Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor. Hum Mol Genet. 2015 Oct 1;24(19):5512-23. PMID: 26199316; PMCID: PMC4572075.

From the abstract: "Environmental factors and susceptible genomes interact to determine the risk of neurodevelopmental disorders. ... Here we focus on the schizophrenia susceptibility gene DTNBP1 and its product dysbindin, a subunit of the BLOC-1 complex, and describe a neuronal pathway modulating copper metabolism via ATP7A. ... Dysbindin/BLOC-1 loss-of-function alleles do not affect cell and tissue copper content, yet they alter the susceptibility to toxic copper challenges in both mammalian cells and Drosophila. Our results demonstrate that perturbations downstream of the schizophrenia susceptibility gene DTNBP1 confer susceptibility to copper, a metal that in excess is a neurotoxin and whose depletion constitutes a micronutrient deficiency."

Review--flies, chromatin remodeling, and intellectual disability & neural disorders

Taniguchi H, Moore AW. Chromatin regulators in neurodevelopment and disease: Analysis of fly neural circuits provides insights: Networks of chromatin regulators and transcription factors underlie Drosophila neurogenesis and cognitive defects in intellectual disability and neuropsychiatric disorder models. Bioessays. 2014 Jul 28. PMID: 25067789.

At least the following disabilities, disorders or syndromes are mentioned in the review (Blogger does not allow tagging the entry with so many characters):  Intellectual disability, Schizophrenia, Autism, CHARGE syndrome, Coffin-Siris syndrome, Kabuki syndrome, Kleefstra syndrome, Maat-Kievit-Brunner syndrome, Nicolaides-Baraitser syndrome, Rubinstein-Taybi syndrome, Say-Barber-Biesecker-Young-Simpson syndrome, Schinzel-Giedion syndrome, Sotos syndrome, Weaver syndrome, Wiedemann-Steiner syndrome

Fly assays included in Fragile X study. Top3beta RNA topoisomerase. Recent report.

Xu D, Shen W, Guo R, Xue Y, Peng W, Sima J, Yang J, Sharov A, Srikantan S, Yang J, Fox D 3rd, Qian Y, Martindale JL, Piao Y, Machamer J, Joshi SR, Mohanty S, Shaw AC, Lloyd TE, Brown GW, Ko MS, Gorospe M, Zou S, Wang W. Top3β is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation. Nat Neurosci. 2013 Sep;16(9):1238-47. PMID: 23912945.