Identification of potential therapeutic compounds for Parkinson's disease using Drosophila and human cell models

Sanz, Francisco; Solana-Manrique, Cristina; Muñoz-Soriano, Verónica; Calap-Quintana, Pablo; Moltó, María Dolores; Paricio, Nuria

doi:10.1016/j.freeradbiomed.2017.04.364

Cited by 38 publications

(83 citation statements)

References 74 publications

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“…Indeed, despite the introduction of 3D cultures, the results obtained with in vitro approaches cannot be generalised in vivo [64]. Drosophila represents a suitable in vivo model with which to perform preliminary drug screening studies to identify new candidate compounds [65,66], while also allowing the investigation of potential side effects, for instance by evaluating the mortality rate, embryonic development, adult morphology and behavioural traits [67,68]. Nonetheless, as drug response profiles can differ between fruit flies and humans due to the evolutionary distance, Drosophila should be considered as a preliminary drug discovery platform, the results of which should be further validated in higher model organisms to clarify their translational relevance.…”

Section: Drosophila As a Model To Evaluate In Vivo Redox Alterationsmentioning

confidence: 99%

Antioxidant Therapy in Parkinson’s Disease: Insights from Drosophila melanogaster

et al. 2020

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Reactive oxygen species (ROS) play an important role as endogenous mediators in several cellular signalling pathways. However, at high concentrations they can also exert deleterious effects by reacting with many macromolecules including DNA, proteins and lipids. The precise balance between ROS production and their removal via numerous enzymatic and nonenzymatic molecules is of fundamental importance for cell survival. Accordingly, many neurodegenerative disorders, including Parkinson’s disease (PD), are associated with excessive levels of ROS, which induce oxidative damage. With the aim of coping with the progression of PD, antioxidant compounds are currently receiving increasing attention as potential co-adjuvant molecules in the treatment of these diseases, and many studies have been performed to evaluate the purported protective effects of several antioxidant molecules. In the present review, we present and discuss the relevance of the use of Drosophila melanogaster as an animal model with which to evaluate the therapeutic potential of natural and synthetic antioxidants. The conservation of most of the PD-related genes between humans and D. melanogaster, along with the animal’s rapid life cycle and the versatility of genetic tools, makes fruit flies an ideal experimental system for rapid screening of antioxidant-based treatments.

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Section: Drosophila As a Model To Evaluate In Vivo Redox Alterationsmentioning

confidence: 99%

Antioxidant Therapy in Parkinson’s Disease: Insights from Drosophila melanogaster

et al. 2020

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“…Therefore, besides the obvious effects due to its glycolytic function, an increase of Hk activity in DJ-1-deficient human cells may play an antioxidant role by leading to G6P-derived NADPH production in response to high ROS levels [24]. Unexpectedly, Hex-A activity was not modified in PD model flies, in which high ROS levels were also detected [12,13].…”

Section: Discussionmentioning

confidence: 93%

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

Solana-Manrique

Sanz

eacutes

et al. 2020

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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.

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“…Invertebrates are key experimental models in a diverse range of research fields from medical biology (Rittschof & Schirmeier, ; Sanz et al, ) to behavioural ecology (Barron & Klein, ; Hollis & Guillette, ; Kralj‐Fišer & Schuett, ). However, despite the importance and widespread use of invertebrates in research, there are few ethical guidelines governing their use in science.…”

Section: Current State Of Ethics For Invertebratesmentioning

confidence: 99%

Keeping invertebrate research ethical in a landscape of shifting public opinion

2019

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Invertebrate study systems are cornerstones of biological and biomedical research, providing key insights into fields from genetics to behavioural ecology. Despite the widespread use of invertebrates in research, there are very few ethical guidelines surrounding their use. Focussing on two ethical considerations faced during invertebrate studies—collecting methods and euthanasia—we make recommendations for integrating principles of vertebrate research into invertebrate research practice. We argue, given emerging research on invertebrate cognition and shifting public perception on the use of invertebrates in research, it is vital that the scientific community revisits the ethics of invertebrate use in research. Without careful consideration and development of the ethics surrounding the use of invertebrates by the scientific community, there is a danger of losing public support. It is imperative that the public understand the significance of research that uses invertebrates and that scientists demonstrate their ethical treatment of their experimental subjects.

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Identification of potential therapeutic compounds for Parkinson's disease using Drosophila and human cell models

Cited by 38 publications

References 74 publications

Antioxidant Therapy in Parkinson’s Disease: Insights from Drosophila melanogaster

Antioxidant Therapy in Parkinson’s Disease: Insights from Drosophila melanogaster

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

Keeping invertebrate research ethical in a landscape of shifting public opinion

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