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

NALCN Channels Are Not Major targets of Gα DOI

Ariana Jose,

Kevin M. Collins

PubMed, Journal Year: 2024, Volume and Issue: 2024

Published: Jan. 1, 2024

Sodium leak channels (NALCN) are regulators of cell membrane potential. Previous studies in mammalian neurons and

Language: Английский

Citations

0
Presynaptic Gαo(GOA-1) signals to depress command neuron excitability and allow stretch-dependent modulation of egg laying inCaenorhabditis elegans DOI Creative Commons
Bhavya Ravi, Jian Zhao, Sana Chaudhry

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2019, Volume and Issue: unknown

Published: July 13, 2019

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 Gα o , conserved Pertussis Toxin-sensitive G protein, within inhibit circuit prevent entry into signaling hyperpolarizes HSN, reducing Ca 2+ 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 -independent mechanisms HSNs -dependent other than HSNs. Thus, neuropeptide maintains bi-stable electrical excitability dynamically controls response both drive output.

Language: Английский

Citations

2
Drebrin-like protein regulates body bending ofC. elegansvia suppression of NCA cation leak channels DOI Open Access
Eugenia Butkevich,

Peter Weist,

Daniel Härtter

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2019, Volume and Issue: unknown

Published: Dec. 13, 2019

Abstract Drebrin-like protein (DBN-1) in C. elegans is an adaptor that connects different cellular pathways to the actin cytoskeleton. Using a CRISPR-Cas9 system, we generated new dbn-1 allele, which lacks 80% of C-terminal part DBN-1. The mutant displays striking hyper-bending locomotion phenotype and body posture with two times stronger curvature than wild type. We show by atomic force microscopy muscle tone remains unaffected. Aiming track down cause hyper-bending, performed genetic epistasis experiments. found mutations Rho-specific guanine-nucleotide exchange factor (GEF) domain UNC-73 (Trio), pan-neuronal expression dominant negative RHO-1 NCA (NALCN) cation leak channels all suppressed mutant. These data indicate DBN-1 negatively regulates activity both NCA-1 NCA-2 channels, opposing non-canonical Gq pathway. conclude important component neuronal signaling cascade controls degree bending during locomotion.

Language: Английский

Citations

2
Systematic creation and phenotyping of Mendelian disease models inC. elegans: towards large-scale drug repurposing DOI Creative Commons
Thomas O’Brien, Ida Barlow, Luigi Feriani

et al.

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

Published: Aug. 28, 2023

Abstract 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

Citations

0
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

Citations

0