Systematic creation and phenotyping of Mendelian disease models in C. elegans: towards large-scale drug repurposing DOI Open Access
Thomas O’Brien, Ida Barlow, Luigi Feriani

et al.

Published: Nov. 28, 2023

There are thousands of Mendelian diseases with more being discovered weekly and the majority have no approved treatments. To address this need, we require scalable approaches that relatively inexpensive compared to traditional drug development. In absence a validated target, phenotypic screening in model organisms provides route for identifying candidate Success requires screenable phenotype, however right phenotype assay may not be obvious pleiotropic neuromuscular disorders. Here show high-throughput imaging quantitative phenotyping can conducted systematically on panel C. elegans disease strains. We used CRISPR genome-editing create 25 worm models human phenotyped them using single standardised assay. All but two strains were significantly different from wild type controls at least one feature. The observed phenotypes diverse, mutations genes predicted related functions their orthologs led similar behavioural differences worms. As proof-of-concept, performed repurposing screen an FDA compound library, identified compounds rescued UNC80 deficiency. Our results measure multiple applied diverse models. short time low cost associated creating suggests tracking could provide approach commensurate number diseases.

Language: Английский

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding DOI
Jan‐Marino Ramirez, Nicholas Burgraff, Aguan Wei

et al.

Journal of Neurophysiology, Journal Year: 2021, Volume and Issue: 125(5), P. 1899 - 1919

Published: April 7, 2021

Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within United States, rate from abuse since early 1990s has grown disproportionally, prompting classification as a nationwide “epidemic.” Since this time, we have begun to unravel many fundamental cellular systems-level mechanisms opioid-related death. However, factors such individual vulnerability, neuromodulatory compensation, redundancy effects across central peripheral nervous systems created barrier concise, integrative view OIRD. review, bring together multiple perspectives in field OIRD create an overarching viewpoint what know, where essential topic research going forward into future.

Language: Английский

Citations

75
New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN DOI
Arnaud Monteil, Nathalie C. Guérineau, António Gil‐Nagel

et al.

Physiological Reviews, Journal Year: 2023, Volume and Issue: 104(1), P. 399 - 472

Published: Aug. 24, 2023

Cell excitability and its modulation by hormones neurotransmitters involve the concerted action of a large repertoire membrane proteins, especially ion channels. Unique complements coexpressed channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that tailored for diverse physiological contributions, dysfunction any component may induce disease state. A crucial parameter controlling is resting potential (RMP) set extra- intracellular concentrations ions, mainly Na + , K Cl − their passive permeation across through leak Indeed, dysregulation RMP causes significant effects on cellular excitability. This review describes molecular channel NALCN, which associates with accessory subunits UNC-79, UNC-80, NLF-1/FAM155 to conduct depolarizing background currents various neurons. Studies animal models clearly demonstrate NALCN contributes fundamental processes nervous system including control respiratory rhythm, circadian sleep, locomotor behavior. Furthermore, associated severe pathological states humans. The critical involvement physiology now well established, but study has been hampered lack specific drugs can block or agonize vitro vivo. Molecular tools available accelerate our understanding how key functions development novel therapies channelopathies.

Language: Английский

Citations

25
Gi/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN DOI Creative Commons

Fabian Philippart,

Zayd M. Khaliq

eLife, Journal Year: 2018, Volume and Issue: 7

Published: Dec. 17, 2018

Dopamine (D2) receptors provide autoinhibitory feedback onto dopamine neurons through well-known interactions with voltage-gated calcium channels and G protein-coupled inwardly-rectifying potassium (GIRK) channels. Here, we reveal a third major effector involved in D2R modulation of dopaminergic - the sodium leak channel, NALCN. We found that activation D2 robustly inhibits isolated currents wild-type mice but not NALCN conditional knockout mice. Intracellular GDP-βS abolished inhibition, indicating protein-dependent signaling mechanism. The application reliably slowed pacemaking even when GIRK were pharmacologically blocked. Furthermore, while spontaneous activity was observed nearly all mice, from knockouts mainly silent. Both observations demonstrate critical importance for neurons. Finally, show GABA-B receptor also produces inhibition NALCN-mediated currents. Therefore, identify as core inhibitory receptors.

Language: Английский

Citations

70
High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models DOI Creative Commons
Thomas O’Brien, Ida Barlow, Luigi Feriani

et al.

eLife, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 8, 2025

There are thousands of Mendelian diseases with more being discovered weekly and the majority have no approved treatments. To address this need, we require scalable approaches that relatively inexpensive compared to traditional drug development. In absence a validated target, phenotypic screening in model organisms provides route for identifying candidate Success requires screenable phenotype. However, right phenotype assay may not be obvious pleiotropic neuromuscular disorders. Here, show high-throughput imaging quantitative phenotyping can conducted systematically on panel C. elegans disease strains. We used CRISPR genome-editing create 25 worm models human phenotyped them using single standardised assay. All but two strains were significantly different from wild-type controls at least one feature. The observed phenotypes diverse, mutations genes predicted related functions led similar behavioural differences worms. As proof-of-concept, performed repurposing screen an FDA-approved compound library, identified compounds rescued UNC80 deficiency. Our results measure multiple applied diverse models. short time low cost associated creating suggest tracking could provide approach commensurate number diseases.

Language: Английский

Citations

0
G protein-coupled receptor kinase-2 (GRK-2) controls exploration through neuropeptide signaling in Caenorhabditis elegans DOI Creative Commons

Kristen C. Davis,

Christo Mitchell,

Olivia Weissenfels

et al.

PLoS Genetics, Journal Year: 2023, Volume and Issue: 19(1), P. e1010613 - e1010613

Published: Jan. 18, 2023

Animals alter their behavior in manners that depend on environmental conditions as well developmental and metabolic states. For example, C . elegans is quiescent during larval molts or of satiety. By contrast, worms enter an exploration state when removed from food. Sensory perception influences movement quiescence (defined a lack body movement), the expression additional locomotor states are associated with increased reduced locomotion activity, such roaming (exploration behavior) dwelling (local search). Here we find enhanced, G protein-coupled receptor kinase grk-2 mutant animals. was previously shown to act chemosensation, locomotion, egg-laying behaviors. Using neuron-specific rescuing experiments, show GRK-2 acts multiple ciliated chemosensory neurons control behavior. opposite ways cGMP-dependent protein gene egl-4 Analysis mutants defects sensory indicates cilium-structure same pathway We controls manner neuropeptide NPR-1 neuropeptides FLP-1 FLP-18. Finally, secretion negatively regulated by overexpression reduces These results define molecular pathways modulate

Language: Английский

Citations

8
Effects of apomorphine, a dopamine agonist, on Daphnia magna: Imaging of swimming track density as a novel tool in the assessment of swimming activity DOI
Adam Bownik,

Natalia Sokołowska,

Brygida Ślaska

et al.

The Science of The Total Environment, Journal Year: 2018, Volume and Issue: 635, P. 249 - 258

Published: April 24, 2018

Language: Английский

Citations

27
Presynaptic Gαo (GOA-1) signals to depress command neuron excitability and allow stretch-dependent modulation of egg laying in Caenorhabditis elegans DOI Open Access
Bhavya Ravi, Jian Zhao, Sana Chaudhry

et al.

Genetics, Journal Year: 2021, Volume and Issue: 218(4)

Published: May 25, 2021

Abstract Egg laying in the nematode worm Caenorhabditis elegans is a two-state behavior modulated by internal and external sensory input. We have previously shown that homeostatic feedback of embryo accumulation uterus regulates bursting activity serotonergic HSN command neurons sustains egg-laying active state. How egg release signals to terminate state less understood. find Gαo, conserved Pertussis Toxin-sensitive G protein, within inhibit circuit prevent entry into Gαo signaling hyperpolarizes HSN, reducing Ca2+ input onto postsynaptic vulval muscles. Loss inhibitory uncouples presynaptic from postsynaptic, stretch-dependent homeostat, causing precocious when only few eggs are present uterus. Feedback opening activates uv1 neuroendocrine cells which NLP-7 neuropeptides signal through Gαo-independent mechanisms HSNs Gαo-dependent other than HSNs. Thus, neuropeptide maintain bi-stable electrical excitability dynamically controls response both drive output.

Language: Английский

Citations

19
Human amyloid beta and α-synuclein co-expression in neurons impair behavior and recapitulate features for Lewy body dementia in Caenorhabditis elegans DOI Creative Commons
Xiaobing Huang, Changliang Wang, Liang Chen

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2021, Volume and Issue: 1867(10), P. 166203 - 166203

Published: June 17, 2021

Language: Английский

Citations

18
Modulation of Gq-Rho Signaling by the ERK MAPK Pathway Controls Locomotion in Caenorhabditis elegans DOI Open Access

Brantley Coleman,

Irini Topalidou, Michael Ailion

et al.

Genetics, Journal Year: 2018, Volume and Issue: 209(2), P. 523 - 535

Published: April 3, 2018

Abstract The heterotrimeric G protein Gq regulates neuronal activity through distinct downstream effector pathways. In addition to the canonical phospholipase Cβ, small GTPase Rho was recently identified as a conserved of Gq. To identify additional molecules important for signaling in neurons, we performed forward genetic screen nematode Caenorhabditis elegans suppressors hyperactivity and exaggerated waveform an activated mutant. We isolated two mutations affecting MAP kinase scaffold KSR-1 found that modulates locomotion of, or parallel to, Gq-Rho pathway. Through epistasis experiments, core ERK MAPK cascade is required regulation locomotion, but activator LET-60/Ras may not be required. neuron-specific rescue pathway functions head acetylcholine neurons control Gq-dependent locomotion. Additionally, expression LIN-45/Raf sufficient cause phenotype hypersensitivity acetylcholinesterase inhibitor aldicarb, similar Taken together, our results suggest output behavior C. elegans.

Language: Английский

Citations

18
Risk Factor Genes in Patients with Dystonia: A Comprehensive Review. DOI
Vasileios Siokas, Athina‐Maria Aloizou,

Zisis Tsouris

et al.

PubMed, Journal Year: 2018, Volume and Issue: 8, P. 559 - 559

Published: Jan. 1, 2018

Dystonia is a movement disorder with high heterogeneity regarding phenotypic appearance and etiology that occurs in both sporadic familial forms. The of the disease remains unknown. However, there increasing evidence suggesting small number gene alterations may lead to dystonia. Although pathogenic variants type dystonia have been extensively reviewed discussed, relatively little known about contribution single-nucleotide polymorphisms (SNPs) This review focuses on potential role SNPs other susceptibility.We searched PubMed database for peer-reviewed articles published English, from its inception through January 2018, concerned human studies genetic variants. following search terms were included: "dystonia" combination terms: 1) "polymorphisms" 2) "SNPs" as free words.A total 43 TOR1A, BDNF, DRD5, APOE, ARSG, NALC, OR4X2, COL4A1, TH, DDC, DBH, MAO, COMT, DAT, GCH1, PRKRA, MR-1, SGCE, ATP1A3, TAF1, THAP1, GNAL, DRD2, HLA-DRB, CBS, MTHFR, MS genes, included current review.To date, few variants, which are possibly involved several molecular pathways, related Large cohort needed determine robust associations between adjustment cofounders, order elucidate mechanisms net effect genes.

Language: Английский

Citations

18