Modeling Neurodegenerative Disorders in Drosophila melanogaster

Bolus, Harris; Crocker, Kassi L.; Boekhoff-Falk, Grace; Chtarbanova, Stanislava

doi:10.3390/ijms21093055

Cited by 69 publications

(39 citation statements)

References 206 publications

(235 reference statements)

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“…In light of the promising results obtained in Aβ 42 anti-aggregating and neuroprotective studies, we evaluated the effect of compound 6 in Drosophila . This is an inexpensive and accessible model for in vivo studies of AD and related neurodegenerative diseases [ 30 , 31 ]. Particularly, the behavioral analysis of flies gives important information about their neuronal condition [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

From Combinations to Single-Molecule Polypharmacology—Cromolyn-Ibuprofen Conjugates for Alzheimer’s Disease

et al. 2021

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Despite Alzheimer’s disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm “one target-one drug-one disease” in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn–ibuprofen drug combination into single-molecule “codrugs.” Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn–ibuprofen conjugates (4–6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aβ42-amyloid self-aggregation, and their cellular neuroprotective effect against Aβ42-induced neurotoxicity. The fact that 6 effectively reduced Aβ-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aβ42-expressing Drosophila and to improve fly locomotor performance.

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Section: Resultsmentioning

confidence: 99%

From Combinations to Single-Molecule Polypharmacology—Cromolyn-Ibuprofen Conjugates for Alzheimer’s Disease

et al. 2021

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“…Animal models have the instrumental role in deciphering the disease mechanisms and in identifying / validating the treatment routes. Drosophila has been used to model a variety of human maladies, especially neurological ones (Bellen et al, 2019;Bolus et al, 2020;Katanaev et al, 2020;Katanaev and Kryuchkov, 2011;Luchtenborg and Katanaev, 2014). As the first step towards modelling GNAO1 paediatric encephalopathies in the fruit fly, we here describe humanization of the Drosophila Gαo locus, finding the human protein fully replaces the insect one's functions without any aberrations.…”

Section: Introductionmentioning

confidence: 98%

Humanization ofDrosophilaGαo to modelGNAO1paediatric encephalopathies

Savitsky

Solis

Katanaev

2020

Preprint

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Several hundred genes have been identified to contribute to epilepsy, the disease affecting 65 million people worldwide. One of these genes is GNAO1 encoding Gαo, the major neuronal α-subunit of heterotrimeric G proteins. An avalanche of dominant de novo mutations in GNAO1 have been recently described in paediatric epileptic patients, suffering in addition to epilepsy from motor dysfunction and developmental delay. Although occurring in amino acids conserved from humans to Drosophila, these mutations and their functional consequences have only poorly been analysed at the biochemical or neuronal levels. Adequate animal models to study molecular aetiology of GNAO1 encephalopathies have also so far been lacking. As the first step towards modelling the disease in Drosophila, we here describe humanization of the Gαo locus in the fruit fly. A two-step CRISPR/Cas9-mediated replacement was conducted, first substituting the coding exons 2-3 of Gαo with respective human GNAO1 sequences. At the next step, the remaining exons 4-7 were similarly replaced, keeping intact the gene Cyp49a1 embedded in-between, as well as the non-coding exon 1 and the surrounding regulatory sequences. The resulting flies, homozygous for the humanized GNAO1 loci, are viable and fertile without any visible phenotypes; their body weight and longevity are also normal. Human Gαo-specific antibodies confirm the endogenous-level expression of the humanized Gαo, which fully replaces the Drosophila functions. The genetic model we established will make it easy to incorporate encephalopathic GNAO1 mutations and will permit intensive investigations into the molecular aetiology of the human disease through the powerful toolkit of Drosophila genetics.

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“…Understanding of mitochondrial roles in disease has been greatly facilitated by the use of simple eukaryotic and animal models, including yeast, slime moulds, nematodes and flies [1][2][3][4][5][6][7][8]. These genetic models are based on gene mutations of genes associated with relatively rare familial neurodegenerative disorders and may not faithfully recapitulate what is happening in the more common sporadic cases of neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

Lymphoblastoid Cell Lines as Models to Study Mitochondrial Function in Neurological Disorders

Annesley

Fisher

2021

IJMS

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Neurological disorders, including neurodegenerative diseases, are collectively a major cause of death and disability worldwide. Whilst the underlying disease mechanisms remain elusive, altered mitochondrial function has been clearly implicated and is a key area of study in these disorders. Studying mitochondrial function in these disorders is difficult due to the inaccessibility of brain tissue, which is the key tissue affected in these diseases. To overcome this issue, numerous cell models have been used, each providing unique benefits and limitations. Here, we focussed on the use of lymphoblastoid cell lines (LCLs) to study mitochondrial function in neurological disorders. LCLs have long been used as tools for genomic analyses, but here we described their use in functional studies specifically in regard to mitochondrial function. These models have enabled characterisation of the underlying mitochondrial defect, identification of altered signalling pathways and proteins, differences in mitochondrial function between subsets of particular disorders and identification of biomarkers of the disease. The examples provided here suggest that these cells will be useful for development of diagnostic tests (which in most cases do not exist), identification of drug targets and testing of pharmacological agents, and are a worthwhile model for studying mitochondrial function in neurological disorders.

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Modeling Neurodegenerative Disorders in Drosophila melanogaster

Cited by 69 publications

References 206 publications

From Combinations to Single-Molecule Polypharmacology—Cromolyn-Ibuprofen Conjugates for Alzheimer’s Disease

From Combinations to Single-Molecule Polypharmacology—Cromolyn-Ibuprofen Conjugates for Alzheimer’s Disease

Humanization ofDrosophilaGαo to modelGNAO1paediatric encephalopathies

Lymphoblastoid Cell Lines as Models to Study Mitochondrial Function in Neurological Disorders

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