Signaling Pathways Involved in 1-Octen-3-ol-Mediated Neurotoxicity in Drosophila melanogaster: Implication in Parkinson’s Disease

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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Kinase signaling pathways: potential therapeutic targets in Parkinson’s disease

Future Neurology ◽

10.2217/14796708.2.1.39 ◽

2007 ◽

Vol 2 (1) ◽

pp. 39-49 ◽

Cited By ~ 3

Author(s):

Robert E Burke

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Signaling Pathways ◽

Therapeutic Targets ◽

Kinase Signaling

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Signaling pathways mediating the neuroprotective effects of sex steroids and SERMs in Parkinson’s disease

Frontiers in Neuroendocrinology ◽

10.1016/j.yfrne.2012.02.003 ◽

2012 ◽

Vol 33 (2) ◽

pp. 169-178 ◽

Cited By ~ 40

Author(s):

Mélanie Bourque ◽

Dean E. Dluzen ◽

Thérèse Di Paolo

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Signaling Pathways ◽

Sex Steroids ◽

Neuroprotective Effects

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The FBXO7 homologue nutcracker and binding partner PI31 in Drosophila melanogaster models of Parkinson’s disease

Genome ◽

10.1139/gen-2016-0087 ◽

2017 ◽

Vol 60 (1) ◽

pp. 46-54 ◽

Cited By ~ 5

Author(s):

Eric M. Merzetti ◽

Lindsay A. Dolomount ◽

Brian E. Staveley

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drosophila Melanogaster ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Severe Form ◽

Altered Expression ◽

Binding Partner ◽

Locomotor Control ◽

Dependent Model

Parkinsonian-pyramidal syndrome (PPS) is an early onset form of Parkinson’s disease (PD) that shows degeneration of the extrapyramidal region of the brain to result in a severe form of PD. The toxic protein build-up has been implicated in the onset of PPS. Protein removal is mediated by an intracellular proteasome complex: an E3 ubiquitin ligase, the targeting component, is essential for function. FBXO7 encodes the F-box component of the SCF E3 ubiquitin ligase linked to familial forms of PPS. The Drosophila melanogaster homologue nutcracker (ntc) and a binding partner, PI31, have been shown to be active in proteasome function. We show that altered expression of either ntc or PI31 in dopaminergic neurons leads to a decrease in longevity and locomotor ability, phenotypes both associated with models of PD. Furthermore, expression of ntc-RNAi in an established α-synuclein-dependent model of PD rescues the phenotypes of diminished longevity and locomotor control.

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An altered microbiome in a Parkinson’s disease model Drosophila melanogaster has a negative effect on development

10.21203/rs.3.rs-909182/v1 ◽

2021 ◽

Author(s):

Jade Parker-Character ◽

David R. Hager ◽

Tanner B. Call ◽

Zachary S. Pickup ◽

Scott A. Turnbull ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drosophila Melanogaster ◽

Disease Model ◽

Model Organism ◽

Fecal Microbiota ◽

Microbiota Composition ◽

Host Genotype ◽

Negative Effect ◽

And Control

Abstract It is well-established that there are differences in the fecal microbiota composition between Parkinson’s disease (PD) patients and control populations, but the mechanisms underlying these differences are not yet fully understood. To begin to close the gap between description and mechanism we studied the relationship between the microbiota and PD in a model organism, Drosophila melanogaster. First, fecal transfers were performed with a D. melanogaster model of PD that had a mutation in the parkin (park25) gene. Results indicate that the PD model feces had a negative effect on both pupation and eclosion in both control and park25 flies, with a greater effect in PD model flies. Analysis of the microbiota composition revealed differences between the control and park25 flies, consistent with many human studies. Conversely, gnotobiotic treatment of axenic embryos with feces-derived bacterial cultures did not affect eclosure. We speculate this result might be due to similarities in bacterial prevalence between mutant and control feces. Further, we confirmed a bacteria-potentiated impact on mutant and control fly phenotypes by measuring eclosure rate in park25flies that were mono-associated with members of the fly microbiota. Both the fecal transfer and the mono-association results indicate a host genotype-microbiota interaction. Overall, this study concludes functional effects of the fly microbiota on PD model flies, providing support to the developing body of knowledge regarding the influence of the microbiota on PD.

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An altered microbiome in a Parkinson’s disease model Drosophila melanogaster has a negative effect on development

Scientific Reports ◽

10.1038/s41598-021-02624-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jade Parker-Character ◽

David R. Hager ◽

Tanner B. Call ◽

Zachary S. Pickup ◽

Scott A. Turnbull ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drosophila Melanogaster ◽

Disease Model ◽

Model Organism ◽

Fecal Microbiota ◽

Microbiota Composition ◽

Host Genotype ◽

Negative Effect ◽

And Control

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease, besides Alzheimer’s Disease, characterized by multiple symptoms, including the well-known motor dysfunctions. It is well-established that there are differences in the fecal microbiota composition between Parkinson’s disease (PD) patients and control populations, but the mechanisms underlying these differences are not yet fully understood. To begin to close the gap between description and mechanism we studied the relationship between the microbiota and PD in a model organism, Drosophila melanogaster. First, fecal transfers were performed with a D. melanogaster model of PD that had a mutation in the parkin (park25) gene. Results indicate that the PD model feces had a negative effect on both pupation and eclosion in both control and park25 flies, with a greater effect in PD model flies. Analysis of the microbiota composition revealed differences between the control and park25 flies, consistent with many human studies. Conversely, gnotobiotic treatment of axenic embryos with feces-derived bacterial cultures did not affect eclosure. We speculate this result might be due to similarities in bacterial prevalence between mutant and control feces. Further, we confirmed a bacteria-potentiated impact on mutant and control fly phenotypes by measuring eclosure rate in park25 flies that were mono-associated with members of the fly microbiota. Both the fecal transfer and the mono-association results indicate a host genotype-microbiota interaction. Overall, this study concludes functional effects of the fly microbiota on PD model flies, providing support to the developing body of knowledge regarding the influence of the microbiota on PD.

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Genome Sequence of Acetobacter tropicalis DmPark25_167, a Bacterium Isolated from a Drosophila melanogaster Genetic Model of Parkinson’s Disease

Microbiology Resource Announcements ◽

10.1128/mra.01138-20 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Julie A. Goddard ◽

Samara C. Petersen ◽

Gerald B. Call ◽

John M. Chaston

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drosophila Melanogaster ◽

Genome Sequence ◽

Bacterial Strain ◽

Genetic Model ◽

Type Iv Secretion ◽

Methionine Metabolism ◽

Content Type ◽

Type Iv

ABSTRACT Here, we report the genome of Acetobacter tropicalis DmPark25_167, a bacterial strain isolated from a Drosophila melanogaster park25 mutant. The park25 mutant is an established genetic model of Parkinson’s disease. DmPark25_167 has duplicated methionine metabolism and type IV secretion gene alleles compared with another strain of A. tropicalis.

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Compound Dihuang Granule Inhibits Nigrostriatal Pathway Apoptosis in Parkinson’s Disease by Suppressing the JNK/AP-1 Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.621359 ◽

2021 ◽

Vol 12 ◽

Author(s):

Li Wang ◽

Yu-fang Yang ◽

Long Chen ◽

Zhu-qing He ◽

Dian-yong Bi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Signaling Pathways ◽

Experimental Validation ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Mapk Signaling ◽

Network Pharmacology ◽

Nigrostriatal Pathway ◽

Bax Protein

Compound Dihuang Granule (CDG) is widely used in traditional Chinese medicine (TCM) for the treatment of Parkinson’s disease (PD). It has been shown to alleviate PD symptoms. However, the molecular mechanisms of its action have not been established. To establish the molecular mechanisms of CDG against PD, we used TCM network pharmacology methods to predict its molecular targets and signaling pathways, followed by experimental validation. The Core Protein protein interaction (PPI) network of the 150 intersections between CDG and PD-related genes, comprising 23 proteins, including CASP3 (caspase-3), MAPK8 (JNK), FOS (c-Fos), and JUN (c-Jun). KEGG and GO analyses revealed that apoptotic regulation and MAPK signaling pathways were significantly enriched. Since c-Jun and c-Fos are AP-1 subunits, an important downstream JNK effector, we investigated if the JNK/AP-1 pathway influences CDG against apoptosis through the nigrostriatal pathways in PD rat models. Molecular docking analysis found that the top three bioactive compounds exhibiting the highest Degree Centrality following online database and LC-MS analysis had high affinities for JNK. Experimental validation analysis showed that CDG decreased the number of rotating laps and suppressed the levels of phosphorylated c-Jun, c-Fos, and JNK, as well as the number of TUNEL positive cells and the cleaved caspase-3 level in the nigrostriatal pathway. Furthermore, CDG treatment elevated the number of TH neurons, TH expression level, and Bcl-2/Bax protein ratio in a 6-OHDA-induced PD rat. These findings are in tandem with those obtained using SP600125, a specific JNK inhibitor. In conclusion, CDG suppresses the apoptosis of the nigrostriatal pathway and relieves PD symptoms by suppressing the JNK/AP-1 signaling pathway.

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