Behavioral Mechanisms That Depend on Dopamine and Serotonin in<i>Caenorhabditis elegans</i>Interact With the Antipsychotics Risperidone and Aripiprazole

Osuna-Luque, Jaime; Rodríguez-Ramos, Ángel; Gámez-del-Estal, María del Mar; Ruiz-Rubio, Manuel

doi:10.1177/1179069518798628

Cited by 12 publications

(9 citation statements)

References 63 publications

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“…Future natural history studies of NGLY1 deficiency should focus on catecholamine insufficiency as a potential driver or axis of pathophysiology. The effects of aripiprazole in worms depends on catecholamine pathway genes (Osuna-Lugue et al, 2018). In flies, aripiprazole was shown to reduce the levels of an aggregated polyglutamine-expanded mutant protein in a model of Machado-Joseph disease, or spinocerebellar ataxia type 3 (Costa et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Drug screens of NGLY1 Deficiency worm and fly models reveal catecholamine, NRF2 and anti-inflammatory pathway activation as potential clinical approaches

Iyer¹,

Mast²,

Tsang³

et al. 2019

Disease Models &Amp; Mechanisms

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N-glycanase 1 (NGLY1) deficiency is an ultra-rare and complex monogenic glycosylation disorder that affects fewer than 40 patients globally. NGLY1 deficiency has been studied in model organisms such as yeast, worms, flies and mice. Proteasomal and mitochondrial homeostasis gene networks are controlled by the evolutionarily conserved transcriptional regulator NRF1, whose activity requires deglycosylation by NGLY1. Hypersensitivity to the proteasome inhibitor bortezomib is a common phenotype observed in whole-animal and cellular models of NGLY1 deficiency. Here, we describe unbiased phenotypic drug screens to identify FDA-approved drugs that are generally recognized as safe natural products, and novel chemical entities, that rescue growth and development of NGLY1-deficient worm and fly larvae treated with a toxic dose of bortezomib. We used image-based larval size and number assays for use in screens of a 2560-member drug-repurposing library and a 20,240-member lead-discovery library. A total of 91 validated hit compounds from primary invertebrate screens were tested in a human cell line in an NRF2 activity assay. NRF2 is a transcriptional regulator that regulates cellular redox homeostasis, and it can compensate for loss of NRF1. Plant-based polyphenols make up the largest class of hit compounds and NRF2 inducers. Catecholamines and catecholamine receptor activators make up the second largest class of hits. Steroidal and non-steroidal anti-inflammatory drugs make up the third largest class. Only one compound was active in all assays and species: the atypical antipsychotic and dopamine receptor agonist aripiprazole. Worm and fly models of NGLY1 deficiency validate therapeutic rationales for activation of NRF2 and anti-inflammatory pathways based on results in mice and human cell models, and suggest a novel therapeutic rationale for boosting catecholamine levels and/or signaling in the brain.

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Section: Discussionmentioning

confidence: 99%

Drug screens of NGLY1 Deficiency worm and fly models reveal catecholamine, NRF2 and anti-inflammatory pathway activation as potential clinical approaches

Iyer¹,

Mast²,

Tsang³

et al. 2019

Disease Models &Amp; Mechanisms

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“…Feeding behavior was reported to be inhibited in C. elegans supporting current study due to the effects of a class of APDs however risperidone was not evaluated for pharyngeal pumping assay in this study ( Donohoe et al, 2006 ). Our results show significant inhibitory effects in pharyngeal pumping mechanism compared to modest effects due to Risperidone (150 μM) and aripiprazole (300 μM) treatment observed in C. elegans ( Osuna-Luque et al, 2018 ). This could be explained due to variation in exposure duration and use of liquid culture assay for drug exposure which requires lesser concentration by increasing bioavailability ( Zheng et al, 2013 ).…”

Section: Discussionmentioning

confidence: 55%

“…A recent study with risperidone and aripiprazole revealed serotonin and dopamine-dependent behavioral alterations in pharyngeal pumping mechanism and gentle touch response wherein C. elegans N2 strain was exposed to 150 μM and 300 μM concentrations respectively ( Osuna-Luque et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Risperidone induced alterations in feeding and locomotion behavior of Caenorhabditis elegans

Gaur

Agarwal

2021

Current Research in Toxicology

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“…As C. elegans is one of the easiest and cheapest multicellular eukaryotic organism to apply precise genome editing to, the choice of this simple nematode for studying PD biology provides fast, cheap in vivo modelling with great translational potential (21,29,51), as discussed throughout this review. C. elegans functional studies of other Mendelian PD genes and their orthologues, including PINK1, Parkin, ATP13A2 and DJ-1, or PD risk genes, such as GBA1, have proven the strength of this invertebrate model, highlighting highly conserved functions of these genes and proteins in cellular pathways disrupted in PD, including mitophagy, lysosomal degradation and α-synuclein pathology (49,134,177,(265)(266)(267)(268)(269)(270)(271)(272)(273). Complex functional interaction of all of these PD proteins and LRRK2 have been described in PD patient samples and in animal models, which supports the idea that LRRK2 is a master regulator of cellular trafficking and quality control pathways, maintaining a crosstalk of a multitude of cellular processes and reflects on the high complexity of Parkinson's pathology (13,(274)(275)(276)(277).…”

Section: Lrrk2 and Beyond: The Potential Of C Elegans For Functional Modelling Of Parkinson's Gwas Candidate Genesmentioning

confidence: 99%

“…C. elegans present a range of PD relevant behavioural and organismal phenotypes to characterise and test, as outputs of gene function, which range from specific dopaminergic neuron attributable behaviours (36,(48)(49)(50), in vivo microscopy (51), to organismal responses to environmental stressors (35), as summarised in Figure 2.…”

mentioning

confidence: 99%

Modelling the functional genomics of Parkinson’s disease inCaenorhabditis elegans:LRRK2and beyond

et al. 2021

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For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans, show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes.

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Behavioral Mechanisms That Depend on Dopamine and Serotonin inCaenorhabditis elegansInteract With the Antipsychotics Risperidone and Aripiprazole

Cited by 12 publications

References 63 publications

Drug screens of NGLY1 Deficiency worm and fly models reveal catecholamine, NRF2 and anti-inflammatory pathway activation as potential clinical approaches

Drug screens of NGLY1 Deficiency worm and fly models reveal catecholamine, NRF2 and anti-inflammatory pathway activation as potential clinical approaches

Risperidone induced alterations in feeding and locomotion behavior of Caenorhabditis elegans

Modelling the functional genomics of Parkinson’s disease inCaenorhabditis elegans:LRRK2and beyond

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