Developmental neurotoxic effects of bisphenol A and its derivatives in Drosophila melanogaster

Ecotoxicology and Environmental Safety, Journal Year: 2023, Volume and Issue: 260, P. 115098 - 115098

Published: June 1, 2023

As a result of the ban on bisphenol A (BPA), hormone disruptor with developmental neurotoxicity, several BPA derivatives (BPs) have been widely used in industrial production. However, there are no effective methods for assessing neurodevelopmental toxic effects BPs. To address this, Drosophila exposure model was established, and W1118 reared food containing these Results showed that each BPs displayed different semi-lethal doses ranging from 1.76 to 19.43 mM. Exposure delayed larval development affected axonal growth, resulting abnormal crossing midline axons β lobules mushroom bodies, but damage caused by BPE BPF relatively minor. BPC, BPAF, BPAP most significant locomotor behavior, whereas BPC exhibited social interactions. Furthermore, high-dose BPA, BPS, also significantly increased expression estrogen-related receptors. These demonstrated kinds had levels toxicity, severity BPZ > BPAF BPB BPS ≈ BPAl BPE. Therefore, BPZ, should be evaluated as potential alternatives BPA.

Language: Английский

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Drosophila expressing mutant human KCNT1 transgenes make an effective tool for targeted drug screening in a whole animal model of KCNT1-epilepsy

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 9, 2024

Abstract Mutations in the KCNT1 potassium channel cause severe forms of epilepsy which are poorly controlled with current treatments. In vitro studies have shown that KCNT1- mutations gain function, significantly increasing K + amplitudes. To investigate if Drosophila can be used to model human , we generated melanogaster lines carrying patient mutation G288S, R398Q or R928C. Expression each mutant GABAergic neurons gave a seizure phenotype responded either positively negatively 5 frontline drugs most commonly administered patients -epilepsy, often little no improvement seizures. Cannabidiol showed greatest reduction while some increased phenotype. Our study shows has potential - and as tool assess new treatments for epilepsy.

Language: Английский

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DHX37 and 46,XY DSD: A New Ribosomopathy?

Sexual Development, Journal Year: 2022, Volume and Issue: 16(2-3), P. 194 - 206

Published: Jan. 1, 2022

Recently, a series of recurrent missense variants in the RNA-helicase <i>DHX37</i> have been reported associated with either 46,XY gonadal dysgenesis, testicular regression syndrome (TRS), or anorchia. All affected children non-syndromic forms disorders/differences sex development (DSD). These variants, which involve highly conserved amino acids within known functional domains protein, are predicted by silico tools to deleterious effect on helicase function. DHX37 is required for ribosome biogenesis eukaryotes, and how these cause DSD unclear. The relationship between human congenital disorders complex as compound heterozygous well de novo also developmental (NEDBAVC, neurodevelopmental disorder brain anomalies without vertebral cardiac anomalies; OMIM 618731), consisting microcephaly, global delay, seizures, facial dysmorphia, kidney anomalies. Here, we will give brief overview role this process. We discuss <i>DHX37</i>, their contribution disease general context ribosomopathies, possible mechanisms that may be involved.

Language: Английский

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α-Synuclein pathology in Drosophila melanogaster is exacerbated by haploinsufficiency of Rop: connecting STXBP1 encephalopathy with α-synucleinopathies

Human Molecular Genetics, Journal Year: 2024, Volume and Issue: 33(15), P. 1328 - 1338

Published: May 1, 2024

Abstract Syntaxin-binding protein 1 (STXBP1) is a presynaptic that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, movement disorders. Most patients with STXBP1-E present regression disorders adulthood, highlighting the importance of deeper understanding neurodegenerative aspects STXBP1-E. An vitro study proposed an interesting new role as molecular chaperone for α-Synuclein (αSyn), key molecule pathogenesis However, no studies have shown αSyn pathology model organisms or In this study, we used Drosophila models to examine effects on αSyn-induced neurotoxicity vivo. We demonstrated Ras opposite (Rop), ortholog STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, dopaminergic neurodegeneration αSyn-expressing flies. This phenotypic aggravation was associated significant increase detergent-insoluble levels head. Furthermore, tested whether trehalose, has neuroprotective various mitigates exacerbated by Rop haploinsufficiency. flies expressing carrying heterozygous null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied decrease conclusion, revealed altering aggregation propensity. not only contributes mechanisms patients, but also provides insights into α-synucleinopathies.

Language: Английский

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Knockdown of Chronophage in the nervous system mimics features of neurodevelopmental disorders caused by BCL11A/B variants

Experimental Cell Research, Journal Year: 2023, Volume and Issue: 433(2), P. 113827 - 113827

Published: Nov. 4, 2023

Language: Английский

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Differential adhesion during development establishes individual neural stem cell niches and shapes adult behaviour in Drosophila

PLoS Biology, Journal Year: 2023, Volume and Issue: 21(11), P. e3002352 - e3002352

Published: Nov. 9, 2023

Neural stem cells (NSCs) reside in a defined cellular microenvironment, the niche, which supports generation and integration of newborn neurons. The mechanisms building sophisticated niche structure around NSCs their functional relevance for neurogenesis are yet to be understood. In Drosophila larval brain, cortex glia (CG) encase individual NSC lineages membranous chambers, organising cell population neurons into stereotypic structure. We first found that CG wrap lineage-related regardless identity, showing lineage information builds architecture. then discovered mechanism temporally controlled differential adhesion using conserved complexes encasing lineages. An intralineage through homophilic Neuroglian interactions provides strong binding between same lineage, while weaker interaction Neurexin-IV Wrapper exists CG. Loss results clumped together an altered network, loss Neurexin-IV/Wrapper generates larger chamber grouping several together. Axonal projections also these conditions. Further, we link 2 specifically during development locomotor hyperactivity resulting adults. Altogether, our findings identify belt adhesions neurogenic at scale provide proof concept properties shape adult behaviour.

Language: Английский

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A clinically‐relevant residue of POLR1D is required for Drosophila development

Developmental Dynamics, Journal Year: 2022, Volume and Issue: 251(11), P. 1780 - 1797

Published: June 3, 2022

POLR1D is a subunit of RNA Polymerases I and III, which synthesize ribosomal RNAs. Dysregulation these polymerases cause several types diseases, including ribosomopathies. The craniofacial disorder Treacher Collins Syndrome (TCS) ribosomopathy caused by mutations in subunits Polymerase I, POLR1D. Here, we characterized the effect missense mutation RNAi knockdown on Drosophila development.We found that (G30R) reduced larval rRNA levels, slowed growth, arrested development. Remarkably, G30R substitution at an orthologous glycine mutated TCS patient (G52E). We showed G52E human POLR1D, comparable (G30E) their ability to heterodimerize with POLR1C vitro. also required early development neural cells. Furthermore, screen revealed for non-neural cells, suggesting possibility defects other cell types.These results establish role development, present as attractive model evaluate molecular

Language: Английский

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A corset of adhesions during development establishes individual neural stem cell niches and controls adult behaviour

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Oct. 5, 2022

ABSTRACT Neural stem cells (NSCs) reside in a defined cellular microenvironment, the niche, which supports generation and integration of neuronal lineages. The mechanisms building sophisticated niche structure around NSCs, their functional relevance for neurogenesis are yet to be understood. In Drosophila larval brain, cortex glia (CG) encase individual NSC lineages, organizing cell population newborn neurons into stereotypic structure. We first found that lineage information is dominant over fate. then discovered that, addition timing, balance between multiple adhesion complexes encasing An intra-lineage through homophilic Neuroglian interactions provides strong binding same lineage, while weaker interaction Neurexin-IV exists CG Their loss leads random, aberrant grouping several lineages together, altered axonal projection neurons. Further, we link these two during development locomotor hyperactivity resulting adults. Altogether, our findings identify corset adhesions neurogenic at scale provide proof-of-principle supporting formation define adult behaviour.

Language: Английский

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Modelling human KCNT1-epilepsy inDrosophila: a seizure phenotype and drug responses

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 12, 2023

Abstract Mutations in the KCNT1 potassium channel cause severe forms of epilepsy which are resistant to current treatments. In vitro studies have shown that KCNT1- mutations gain function, significantly increasing K + amplitudes. To investigate if Drosophila can be used model human epilepsy, we generated melanogaster lines carrying with patient mutation G288S, R398Q or R928C. Expression each mutant GABAergic neurons gave a seizure phenotype was sensitive drugs currently treat patients -epilepsy. Cannabidiol showed greatest reduction while some increased phenotype. Our study shows -epilepsy and potentially as tool assess new treatments for epilepsy.

Language: Английский

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