Drosophila as a Model System for the Identification of Pharmacological Therapies in Neurodegenerative Diseases

Solana-Manrique, Cristina; Moltó, María Dolores; Calap-Quintana, Pablo; Sanz, Francisco; Llorens, José Vicente; Paricio, Nuria

doi:10.1007/978-981-13-2218-1_15

Cited by 7 publications

(7 citation statements)

References 150 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The major advantages of C. elegans are their rapid growth rate and their cost-effectiveness as a model for the detection of compounds that have a protective effect(s) against the harmful impacts of the accumulated misfolded proteins in the neurons of patients suffering from NDDs such as ALS [ 120 ], Huntington’s disease (HD) [ 121 ], PD [ 122 ], and AD [ 123 , 124 ]. Another example is Drosophila melanogaster [ 125 , 126 ], which has similar advantages offered by zebrafish and C. elegans such as the rapid growth rate, amenability for genetic modifications, and successful application as a model of NDDs in HTS [ 127 , 128 , 129 ]. However, all of these models suffer from a common major drawback, the limited ability to effectively mimic the complex pathophysiological environment of NDDs in humans.…”

Section: Drugs Discovery For Nddsmentioning

confidence: 99%

High-Throughput Screening Platforms in the Discovery of Novel Drugs for Neurodegenerative Diseases

et al. 2021

View full text Add to dashboard Cite

Neurodegenerative diseases (NDDs) are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells in the central nervous system (CNS). Identification of viable therapeutic targets and new treatments for CNS disorders and in particular, for NDDs is a major challenge in the field of drug discovery. These difficulties can be attributed to the diversity of cells involved, extreme complexity of the neural circuits, the limited capacity for tissue regeneration, and our incomplete understanding of the underlying pathological processes. Drug discovery is a complex and multidisciplinary process. The screening attrition rate in current drug discovery protocols mean that only one viable drug may arise from millions of screened compounds resulting in the need to improve discovery technologies and protocols to address the multiple causes of attrition. This has identified the need to screen larger libraries where the use of efficient high-throughput screening (HTS) becomes key in the discovery process. HTS can investigate hundreds of thousands of compounds per day. However, if fewer compounds could be screened without compromising the probability of success, the cost and time would be largely reduced. To that end, recent advances in computer-aided design, in silico libraries, and molecular docking software combined with the upscaling of cell-based platforms have evolved to improve screening efficiency with higher predictability and clinical applicability. We review, here, the increasing role of HTS in contemporary drug discovery processes, in particular for NDDs, and evaluate the criteria underlying its successful application. We also discuss the requirement of HTS for novel NDD therapies and examine the major current challenges in validating new drug targets and developing new treatments for NDDs.

show abstract

Section: Drugs Discovery For Nddsmentioning

confidence: 99%

High-Throughput Screening Platforms in the Discovery of Novel Drugs for Neurodegenerative Diseases

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Once determined the effectiveness of MEC and DMF in DJ-1-deficient cells, we tested their effect in phenotypes displayed by PD model flies. Drosophila offers a more convenient way to evaluate the therapeutic potential of compounds since they can be tested in a whole organism context [49]. It was previously reported that DJ-1β mutants exhibited impaired motor performance, high ROS production as well as elevated protein carbonylation levels [11][12][13], phenotypes that were shown to be suppressed by treatments with potential therapeutic compounds [13,24].…”

Section: Meclizine and Dimethyl Fumarate Suppress Phenotypes And Enhance Glycolysis In Dj-1β Mutant Flies By Increasing Pfk Activitymentioning

confidence: 99%

Enhanced activity of glycolytic enzymes in Drosophila and human cell models of Parkinson's disease based on DJ-1 deficiency

Solana-Manrique

Sanz

Ripollés

et al. 2020

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

Parkinson's disease (PD) is a neurodenerative debilitating disorder characterized by progressive disturbances in motor, autonomic and psychiatric functions. The pathological hallmark of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta, which causes striatal dopamine deficiency. Although most PD cases are sporadic (iPD), approximately 5-10% of all patients suffer from monogenic PD forms caused by highly penetrant rare mutations segregating with the disease in families (fPD). One of the genes linked to monogenic PD is DJ-1. Mutations in DJ-1 cause autosomal recessive early-onset forms of fPD; however, it has been shown that an over-oxidized and inactive form of the DJ-1 protein is found in the brains of iPD individuals. Valuable insights into potential PD pathogenic mechanisms involving DJ-1 have been obtained from studies in cell and animal PD models based on DJ-1 deficiency such as Drosophila. Flies mutant for the DJ-1β gene, the Drosophila ortholog of human DJ-1, exhibited disease-related phenotypes such as motor defects, increased reactive oxygen species production and high levels of protein carbonylation. In the present study, we show that loss of DJ-1β function significantly increased the activities of several regulatory glycolytic enzymes. Similar results were obtained in DJ-1-deficient SH-SY5Y neuroblastoma cells, thus suggesting that loss of DJ-1 function in both PD models produces an enhancement of glycolysis. Our results also show that FDA-approved compounds such as meclizine and dimethyl fumarate, which have different clinical applications, are able to attenuate PD-related phenotypes in both models.Moreover, we found that they could exert their beneficial effect by increasing glycolysis through the activation of key glycolytic enzymes. Taken together, these results are consistent with the idea that increasing glycolysis could be a potential disease-modifying strategy for PD, as recently suggested. Besides, they also support further evaluation and potential repurposing of meclizine and dimethyl fumarate as modulators of energy metabolism for neuroprotection in PD.

show abstract

“…4D), thus indicating that PD-related phenotypes in DJ-1ß mutants could be caused in part by dysregulation of Ca 2+ homeostasis. Although Drosophila is a valuable organism that allows to test the effect of compounds in living organisms, those shown to be beneficial in flies should be validated in mammalian models (Solana-Manrique et al, 2019). Thus, to determine the translatability of the results obtained in PD model flies, we performed cell viability assays in DJ-1- deficient cells pretreated with five concentrations of CDN1163 (in a range 1-50 μM) in OS conditions (see Materials and Methods section).…”

Section: Resultsmentioning

confidence: 99%

SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

Solana-Manrique

Muñoz-Soriano

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

DJ-1 is a causative gene for familial Parkinson’s disease (PD) with different functions, standing out its role against oxidative stress (OS). Accordingly, PD model flies harboring a mutation in the DJ-1β gene (the Drosophila ortholog of human DJ-1) show high levels of OS markers like protein carbonylation, a common post-translational modification that may alter protein function. To increase our understanding of PD pathogenesis as well as to discover potential therapeutic targets for pharmacological intervention, we performed a redox proteomic assay in DJ-1β mutant flies. Among the proteins that showed increased carbonylation levels in PD model flies, we found SERCA, an endoplasmic reticulum Ca2+ channel that plays an important role in Ca2+ homeostasis. Several studies have supported the involvement of Ca2+ dyshomeostasis in PD. Interestingly, a functional link between DJ-1 and Ca2+ homeostasis maintenance was previously reported. Thus, we decided to study the relation between SERCA activity and PD physiopathology. Our results showed that SERCA enzymatic activity is significantly reduced in DJ-1β mutant flies, probably as a consequence of OS-induced carbonylation, as well as in a human cell PD model based on DJ-1-deficiency. Indeed, higher carbonylation levels of SERCA were also observed in DJ-1-deficient SH-SY5Y neuron-like cells compared to controls. In addition, we demonstrated that SERCA activity was increased in both PD models after treatment with a specific activator of this protein, CDN1163. Consistently, CDN1163 was also able to restore PD-related phenotypes in PD model flies and to increase viability in the human cell PD model. Taken together, our results indicate that impaired SERCA activity in both familial PD models may play a role in PD physiopathology. In addition, we demonstrate that therapeutic strategies addressing SERCA activation could be beneficial to treat this disease as shown for CDN1163.

show abstract

Drosophila as a Model System for the Identification of Pharmacological Therapies in Neurodegenerative Diseases

Cited by 7 publications

References 150 publications

High-Throughput Screening Platforms in the Discovery of Novel Drugs for Neurodegenerative Diseases

High-Throughput Screening Platforms in the Discovery of Novel Drugs for Neurodegenerative Diseases

Enhanced activity of glycolytic enzymes in Drosophila and human cell models of Parkinson's disease based on DJ-1 deficiency

SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

Contact Info

Product

Resources

About