Novel Drosophila model for psychiatric disorders including autism spectrum disorder by targeting of ATP-binding cassette protein A

Ueoka, Ibuki; Kawashima, Hitoshi; Konishi, Akio; Aoki, Mikio; Tanaka, Ryo; Yoshida, Hideki; Maeda, Toru; Ozaki, Mamiko; Yamaguchi, Masamitsu

doi:10.1016/j.expneurol.2017.10.027

Cited by 28 publications

(20 citation statements)

References 18 publications

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“…CG1718 pan-neuronal knockdown flies were recently established as a model for autism spectrum disorder. These flies exhibited behavioral characteristics similar to those observed in human autism spectrum disorder patients, and showed excessive synaptic satellite bouton outgrowths ( Ueoka et al 2018 ), similar to those in Fmr1 mutants ( Zhang et al 2001 ). The Fmr1 gene has been reported to play a role in glial phagocytosis of neuronal and axonal debris, and in hemocyte phagocytosis of bacteria ( Logan 2017 ; O’Connor et al 2017 ), and thus, by analogy, CG1718 may similarly play a phagocytic role in cell clearance, though likely not in engulfing glia ( Ziegenfuss 2012 ).…”

Section: Discussionsupporting

confidence: 57%

“…CG1718 encodes another ABCA protein that is expressed in the ovary, and has been proposed as the D. melanogaster homolog of ABCA1 for its role in lipid and cholesterol homeostasis ( Bujold et al 2010 ), and the homolog of ced-7 in cell clearance ( Ziegenfuss 2012 ; Nainu et al 2017 ). Additionally, while studies in engulfing glia did not find a role for CG1718 in neuronal corpse or axonal debris clearance ( Ziegenfuss 2012 ), pan-neuronal-specific knockdown of CG1718 resulted in synaptic bouton overgrowth at the neuromuscular junction ( Ueoka et al 2018 ). To determine whether CG1718 plays a role in NC clearance, we quantified PN in CG1718 knockdowns and mutants.…”

Section: Resultsmentioning

confidence: 99%

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The ABC Transporter Eato Promotes Cell Clearance in the Drosophila melanogaster Ovary

Santoso

Meehan

Peterson

et al. 2018

G3 Genes|Genomes|Genetics

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The clearance of dead cells is a fundamental process in the maintenance of tissue homeostasis. Genetic studies in Drosophila melanogaster, Caenorhabditis elegans, and mammals have identified two evolutionarily conserved signaling pathways that act redundantly to regulate this engulfment process: the ced-1/-6/-7 and ced-2/-5/-12 pathways. Of these engulfment genes, only the ced-7/ABCA1 ortholog remains to be identified in D. melanogaster. Homology searches have revealed a family of putative ced-7/ABCA1 homologs encoding ATP-binding cassette (ABC) transporters in D. melanogaster. To determine which of these genes functions similarly to ced-7/ABCA1, we analyzed mutants for engulfment phenotypes in oogenesis, during which nurse cells (NCs) in each egg chamber undergo programmed cell death (PCD) and are removed by neighboring phagocytic follicle cells (FCs). Our genetic analyses indicate that one of the ABC transporter genes, which we have named Eato (Engulfment ABC Transporter in the ovary), is required for NC clearance in the ovary and acts in the same pathways as drpr, the ced-1 ortholog, and in parallel to Ced-12 in the FCs. Additionally, we show that Eato acts in the FCs to promote accumulation of the transmembrane receptor Drpr, and promote membrane extensions around the NCs for their clearance. Since ABCA class transporters, such as CED-7 and ABCA1, are known to be involved in lipid trafficking, we propose that Eato acts to transport membrane material to the growing phagocytic cup for cell corpse clearance. Our work presented here identifies Eato as the ced-7/ABCA1 ortholog in D. melanogaster, and demonstrates a role for Eato in Drpr accumulation and phagocytic membrane extensions during NC clearance in the ovary.

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Section: Discussionsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

The ABC Transporter Eato Promotes Cell Clearance in the Drosophila melanogaster Ovary

Santoso

Meehan

Peterson

et al. 2018

G3 Genes|Genomes|Genetics

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“…AZ is an important structure for the exchange of chemicals at synapses in which the release of neurochemicals onto postsynaptic receptors is precisely controlled 29,30 . Alterations in AZs have been observed in various Drosophila disease models, particularly in neurological disorders, such as ALS, FTD, and ASD 21,31,32 . The immunostaining signals of Bruchpilot (Brp), one of the synaptic proteins located at the AZs of the Drosophila NMJs, were attenuated in the Drosophila model of ALS and Pitt-Hopkins syndrome 33,34 .…”

Section: Resultsmentioning

confidence: 99%

“…Brp is an important synaptic protein located in the AZs of neurotransmitter release sites 46,47 . Alterations in AZs have been found in various types of animal models related to neurological disorders, such as ALS, Pitt-Hopkins syndrome, and ASD 21,33,34 . Since dUbqn-depleted flies showed locomotive defects 20 , reductions in Brp may reflect synaptic defects in dUbqn-depleted flies that already exhibit difficulty with movement.…”

Section: Discussionmentioning

confidence: 99%

The depletion of ubiquilin in Drosophila melanogaster disturbs neurochemical regulation to drive activity and behavioral deficits

Jantrapirom

Enomoto

Karinchai

et al. 2020

Sci Rep

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Drosophila melanogaster is a useful and highly tractable model organism for understanding the molecular mechanisms of human diseases. We previously characterized a new dUbqn knockdown model that induces learning-memory and locomotive deficits mediated by impaired proteostasis. Although proteinopathies are the main causes of neurodegenerative diseases, limited information is currently available on the relationship between proteostasis and neurodegenerative-related behavioral perturbations, such as locomotion, wakefulness, and sexual activities. Thus, the present study aimed to elucidate the mechanisms by which dUbqn depletion which is known to cause proteinopathies, affects neurodegenerative-related behavioral perturbations. pan-neuronal dUbqn-depleted flies showed significantly reduced evening activity along with altered pre-and postsynaptic structural NMJ's proteins by attenuating signals of Bruchpilot puncta and GluRIIA clustering. In addition, the neurochemical profiles of GABA, glutamate, dopamine, and serotonin were disturbed and these changes also affected courtship behaviors in dUbqn-depleted flies. Collectively, these results extend our understanding on how dUbqn depletion affects neurochemical regulation to drive behavioral disturbances that are generally found in the early stage of neurodegenerative diseases. Moreover, the present study may contribute a novel finding to the design of new agents that prevent disease progression or even treat diseases related to neurodegeneration. An effective regulation of proteostasis is a fundamental requirement for cells, particularly neurons, which are highly susceptible to proteotoxicity. Disruptions in protein turnover by stressors, gene mutations, or even a normal aging process have been shown to accelerate the development of proteinopathy-related disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) 1-3. Neuronal-related symptoms, including motor, cognitive, and behavioral alterations, manifest in the early stages of neurodegenerative progression 4,5. However, the mechanisms underlying these early symptoms have not yet been elucidated in detail. Ubiquilins (UBQLNs), an important group of the proteins involved in proteostasis, has been extensively studied in a wide spectrum of neurodegenerative disorders. They are characterized as Ubiquitin-like (UbL)-Ubiquitin-associated (UbA) proteins that recognize and bind to ubiquitylated substrates in order to target them for degradation via proteasomes, endoplasmic reticulum-associated protein degradation (ERAD), and macroautophagy 6-9. The five human UBQLNs homologues such as UBQLN1, UBQLN2, UBQLN3, UBQLN4 and UBQLNL have been established so far. However, only mutations in UBQLN2 and UBQLN4 strongly associate to ALS or ALS/FTD. Besides, UBQLNs also exhibit several distinctive activities, such as an actin and intermediate filament association, cell survival regulation by coordinating with protein-disulfide isomerase (PDI), and their emer...

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“…In contrast, other studies have indicated that there was no association between copy number variants in ABCA13 and schizophrenia or bipolar disorder (Pickard et al, 2012; Degenhardt et al, 2013). While experimental animals with ABCA knock‐down have revealed this gene may regulate the formation and/or maintenance of the presynaptic terminals of the motor neurons for psychiatric model of ASD (Ueoka et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

The neuropathological investigation of the brain in a monkey model of autism spectrum disorder with ABCA13 deletion

Iritani

Torii

Habuchi

et al. 2018

Intl J of Devlp Neuroscience

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The precise biological etiology of autism spectrum disorder (ASD) remains unknown. In this study, we investigated the neuropathology of a monkey model of autism Human ABCA13 is the largest ABC transporter protein, with a length of 5058 amino acids and a predicted molecular weight of >450 kDa. However, the function of this protein remains to be elucidated. This protein is thought to be associated with major psychiatric disease. Using this monkey model of autism with an ABCA13 deletion and a mutation of 5HT2c, we neuropathologically investigated the changes in the neuronal formation in the frontal cortex. As a result, the neuronal formation in the cortex was found to be disorganized with regard to the neuronal size and laminal distribution in the ABCA13 deletion monkey. The catecholaminergic and GABAergic neuronal systems, serotoninergic neuronal formation (5HT2c) were also found to be impaired by an immunohistochemical evaluation. This study suggested that ABCA13 deficit induces the impairment of neuronal maturation or migration, and the function of the neuronal network. This protein might thus play a role in the neurodevelopmental function of the central nervous system and the dysfunction of this protein may be a pathophysiological cause of mental disorders including autism.

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Novel Drosophila model for psychiatric disorders including autism spectrum disorder by targeting of ATP-binding cassette protein A

Cited by 28 publications

References 18 publications

The ABC Transporter Eato Promotes Cell Clearance in the Drosophila melanogaster Ovary

The ABC Transporter Eato Promotes Cell Clearance in the Drosophila melanogaster Ovary

The depletion of ubiquilin in Drosophila melanogaster disturbs neurochemical regulation to drive activity and behavioral deficits

The neuropathological investigation of the brain in a monkey model of autism spectrum disorder with ABCA13 deletion

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