ex-vivo-calcium-imaging-for-drosophila-model-of-epilepsy

<em>Ex Vivo</em> Calcium Imaging for <em>Drosophila</em> Model of Epilepsy

Epilepsy is a neurological disorder characterized by recurrent seizures, partially correlated with genetic origin, affecting over 70 million individuals ...

The Third Affiliated Hospital of Guangzhou Medical University

Impairment of the dopamine system is the main cause of Parkinson disease (PD). PTEN-induced kinase 1 (PINK1) is possibly involved in pathogenesis of PD. However, its role in dopaminergic neurons has not been fully established yet. In the present investigation, we have used the PINK1 knockout Drosophila model to explore the role of PINK1 in dopaminergic neurons. Electrophysiological and behavioral tests indicated that PINK1 elimination enhances the neural transmission from the presynaptic part of dopaminergic neurons in the protocerebral posterior medial region 3 (PPM3) to PPM3 neurons (which are homologous to those in the substantia nigra in humans). Firing properties of the action potential in PPM3 neurons were also altered in the PINK1 knockout genotypes. Abnormal motor ability was also observed in these PINK1 knockout animals. Our results indicate that knockout of PINK1 could alter both the input and output properties of PPM3 neurons.

Knockout of PINK1 altered the neural connectivity of Drosophila dopamine PPM3 neurons at input and output sites.

LRP1, the low-density lipoprotein receptor 1, would be a novel candidate gene of epilepsy according to our bioinformatic results and the animal study. In this study, we explored the role of LRP1 in epilepsy and whether beta-hydroxybutyrate, the principal ketone body of the ketogenic diet, can treat epilepsy caused by LRP1 deficiency in drosophila. UAS/GAL4 system was used to establish different genotype models. Flies were given standard, high-sucrose, and ketone body food randomly. The bang-sensitive test was performed on flies and seizure-like behavior was assessed. In morphologic experiments, we found that LRP1 deficiency caused partial loss of the ellipsoidal body and partial destruction of the fan-shaped body. Whole-body and glia LRP1 defect flies had a higher seizure rate compared to the control group. Ketone body decreased the seizure rate in behavior test in all LRP1 defect flies, compared to standard and high sucrose diet. Overexpression of glutamate transporter gene Eaat1 could mimic the ketone body effect on LRP1 deficiency flies. This study demonstrated that LRP1 defect globally or in glial cells or neurons could induce epilepsy in drosophila. The ketone body efficaciously rescued epilepsy caused by LRP1 knockdown. The results support screening for LRP1 mutations as discriminating conduct for individuals who require clinical attention and further clarify the mechanism of the ketogenic diet in epilepsy, which could help epilepsy patients make a precise treatment case by case.

Ketone Body Rescued Seizure Behavior of LRP1 Deficiency in Drosophila by Modulating Glutamate Transport.

YWHAZ encodes an adapter protein 14-3-3ζ, which is involved in many signaling pathways that control cellular proliferation, migration and differentiation. It has not been definitely correlated to any phenotype in OMIM. To investigate the role of YWHAZ gene in intellectual disability and global developmental delay, we conducted whole-exon sequencing in all of the available members from a large three-generation family and we discovered that a novel variant of the YWHAZ gene was associated with intellectual disability and global developmental delay. This variant is a missense mutation of YWHAZ, p.Lys49Asn/c.147A > T, which was found in all affected members but not found in other unaffected members. We also conducted computational modeling and knockdown/knockin with Drosophila to confirm the role of the YWHAZ variant in intellectual disability. Computational modeling showed that the binding energy was increased in the mutated protein combining with the ligand indicating that the c147A > T variation was a loss-of-function variant. Cognitive defects and mushroom body morphological abnormalities were observed in YWHAZ c.147A > T knockin flies. The YWHAZ knockdown flies also manifested serious cognitive defects with hyperactivity behaviors, which is consistent with the clinical features. Our clinical and experimental results consistently suggested that YWHAZ was a novel intellectual disability pathogenic gene.

YWHAZ variation causes intellectual disability and global developmental delay with brain malformation.

The objective of this study was to explore the clinical application of noninvasive chromosomal screening (NICS) for elective single-blastocyst transfer (eSBT) in frozen-thawed cycles.

Clinical application of noninvasive chromosomal screening for elective single-blastocyst transfer in frozen-thawed cycles.

Correction to: Ketone Body Rescued Seizure Behavior of LRP1 Deficiency in Drosophila by Modulating Glutamate Transport.

Blastocyst developmental speed, morphological grading and patient age are associated with pregnancy outcomes of frozen-thawed cycles. This study aimed to compare the clinical and neonatal outcomes between poor-quality D5 blastocysts and good-quality D6 blastocysts stratified by patient age.

No advantage of single day 6 good-quality blastocyst transfer versus single day 5 poor-quality blastocyst transfer in frozen-thawed cycles stratified by age: a retrospective study.

It has been established that  encodes E3 ubiquitin ligase, which determines the specificity of substrate binding during protein ubiquitination and has been associated with various functions of the nervous system but not the reproductive system. Herein, we explored the role of  on fertility with a .

Article	Year
Knockout of PINK1 altered the neural connectivity of Drosophila dopamine PPM3 neurons at input and output sites. Invertebrate neuroscience : IN\| PubMed ID: 32766952	2020
Ketone Body Rescued Seizure Behavior of LRP1 Deficiency in Drosophila by Modulating Glutamate Transport. Journal of molecular neuroscience : MN\| PubMed ID: 35668313	2022
YWHAZ variation causes intellectual disability and global developmental delay with brain malformation. Human molecular genetics\| PubMed ID: 36001342	2023
Clinical application of noninvasive chromosomal screening for elective single-blastocyst transfer in frozen-thawed cycles. Journal of translational medicine\| PubMed ID: 36463184	2022
Correction to: Ketone Body Rescued Seizure Behavior of LRP1 Deficiency in Drosophila by Modulating Glutamate Transport. Journal of molecular neuroscience : MN\| PubMed ID: 36572796	2023
No advantage of single day 6 good-quality blastocyst transfer versus single day 5 poor-quality blastocyst transfer in frozen-thawed cycles stratified by age: a retrospective study. BMC pregnancy and childbirth\| PubMed ID: 36717810	2023
deficiency causes male sterility and testis abnormal in . Frontiers in endocrinology\| PubMed ID: 37529615	2023

Yu-Ling Mao

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