Parkinson’s Disease Associated α-Synuclein Familial Mutants Promote Dopaminergic Neuronal Death in <i>Drosophila melanogaster</i>

Mohite, Ganesh M.; Dwivedi, Saumya; Das, Subhadeep; Kumar, Rakesh; Paluri, Sravya; Mehra, Surabhi; Ruhela, Neha; Sakunthala, Arunima; Jha, Narendra Nath; Maji, Samir K.

doi:10.1021/acschemneuro.8b00107

Cited by 30 publications

(30 citation statements)

References 52 publications

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“…Drosophila models of PD expressing not only WT αSyn but also some familial PD-linked forms of mutant αSyn, such as A30P, E46K, H50Q, G51D, and A53T, have been previously established by random transgenesis [25,33,38]. A30P αSyn-expressing flies were reported to demonstrate stronger phenotypes than WT αSyn-expressing flies, although expression levels of the transgenes were not analyzed [33].…”

Section: Discussionmentioning

confidence: 99%

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E46K mutant α-synuclein is more degradation resistant and exhibits greater toxic effects than wild-type α-synuclein in Drosophila models of Parkinson's disease

Sakai¹,

Suzuki²,

Ueyama³

et al. 2019

PLoS ONE

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Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, which is characterized by progressive motor dysfunction as well as non-motor symptoms. Pathological and genetic studies have demonstrated that α-synuclein (αSyn) plays key roles in the pathogenesis of PD. Although several missense mutations in the αSyn gene have been identified as causes of familial PD, the mechanisms underlying the variance in the clinical phenotypes of familial PD caused by different mutations remain elusive. Here, we established novel Drosophila models expressing either wild-type (WT) αSyn or one of five αSyn mutants (A30P, E46K, H50Q, G51D, and A53T) using site-specific transgenesis, which express transgenes at equivalent levels. Expression of either WT or mutant αSyn in the compound eyes by the GMR-GAL4 driver caused mild rough eye phenotypes with no obvious difference among the mutants. Upon pan-neuronal expression by the nSyb-GAL4 driver, these αSyn-expressing flies showed a progressive decline in locomotor function. Notably, we found that E46K, H50Q, G51D, and A53T αSyn-expressing flies showed earlier onset of locomotor dysfunction than WT αSyn-expressing flies, suggesting their enhanced toxic effects. Whereas mRNA levels of WT and mutant αSyn were almost equivalent, we found that protein expression levels of E46K αSyn were higher than those of WT αSyn. In vivo chase experiments using the drug-inducible GMR-GeneSwitch driver demonstrated that degradation of E46K αSyn protein was significantly slower than WT αSyn protein, indicating that the E46K αSyn mutant gains resistance to degradation in vivo . We therefore conclude that our novel site-specific transgenic fly models expressing either WT or mutant αSyn are useful to explore the mechanisms by which different αSyn mutants gain toxic functions in vivo .

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Section: Discussionmentioning

confidence: 99%

“…Mohite et al . also established flies expressing each of E46K, H50Q, and G51D by random transgenesis, and analyzed the fly lines with equivalent protein expression levels [38]. Their E46K, H50Q, and G51D αSyn-expressing flies showed more severe declines in locomotor function than WT αSyn-expressing flies.…”

Section: Discussionmentioning

confidence: 99%

E46K mutant α-synuclein is more degradation resistant and exhibits greater toxic effects than wild-type α-synuclein in Drosophila models of Parkinson's disease

Sakai¹,

Suzuki²,

Ueyama³

et al. 2019

PLoS ONE

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“…The disruption of the enzymatic antioxidant system is followed by mitochondrial damage via depletion of NPSH and in turn enhances the production of free radicals [54]. Proteotoxicity and the dopaminergic neuronal death in Drosophila due to the expression of alpha synuclein and lewy bodies are well established [55, 56, 57, 58]. We found that PD flies exposed to MB showed decreased TBARS levels which were accompanied by decreased SOD and CAT activity followed by increased NPSH levels.…”

Section: Resultsmentioning

confidence: 78%

Effect of Majun Baladur on life span, climbing ability, oxidative stress and dopaminergic neurons in the transgenic Drosophila model of Parkinson's disease

Siddique

Naz

Rahul

et al. 2019

Heliyon

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The effect of a poly herbal drug Majun Baladur (MB) was studied on the transgenic Drosophila melanogaster expressing human alpha synuclein in the neurons (PD flies). The equivalents of recommended dose for human were established for 20 g of fly food i.e. 0.0014, 0.0028, 0.0042 and 0.0056 g per 20 g of diet. The PD flies were allowed to feed on it for 24 days before performing the assays. The exposure to MB increased the life span and improves the activity of PD flies. The PD flies exposed to 0.0014, 0.0028, 0.042 and 0.0056 g of MB showed a dose dependent significant delay of 1.47, 1.88, 2.52 and 3.05 folds in the climbing ability compared to unexposed PD flies. A dose dependent significant decrease of 1.38, 1.45, 1.48 and 1.65 folds in TBARS; 1.08, 1.11, 1.17 and 1.20 folds in the GST activity; 1.20, 1.28, 1.39 and 1.52 folds in the PC content; 1.43, 1.53, 1.65 and 1.79 folds in the Caspase-9 activity; 1.21, 1.31, 1.53 and 1.64 folds in the activity of Caspase-3 and 1.24, 1.42, 1.50 and 1.79 folds in the activity of catalase; 1.50, 1.63, 1.88 and 2.06 folds in the activity of SOD in PD flies exposed to 0.0014, 0.0028, 0.042 and 0.0056 g of MB, respectively. A significant dose dependent increase of 1.20, 1.29, 1.33 and 1.44 folds in as NPSH content was observed in PD flies exposed to 0.0014, 0.0028, 0.042 and 0.0056 g of MB, respectively. The exposure to MB protects the loss of dopaminergic neurons as is evident by immunohistochemistry. It is concluded that MB is potent in reducing the PD symptoms being mimicked in the transgenic flies.

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“…A30P or G51D flies have a lower climbing ability than normal flies (23,24). Saffron and crocetin significantly suppressed the decrease of climbing ability in the A30P flies ( Fig.…”

Section: Resultsmentioning

confidence: 86%

Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson’s diseasein vivo

Inoue¹,

Suzuki

Shimizu³

et al. 2020

Preprint

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Parkinson’s disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in A30P fly PD model in eye. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.

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Parkinson’s Disease Associated α-Synuclein Familial Mutants Promote Dopaminergic Neuronal Death in Drosophila melanogaster

Cited by 30 publications

References 52 publications

E46K mutant α-synuclein is more degradation resistant and exhibits greater toxic effects than wild-type α-synuclein in Drosophila models of Parkinson's disease

E46K mutant α-synuclein is more degradation resistant and exhibits greater toxic effects than wild-type α-synuclein in Drosophila models of Parkinson's disease

Effect of Majun Baladur on life span, climbing ability, oxidative stress and dopaminergic neurons in the transgenic Drosophila model of Parkinson's disease

Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson’s diseasein vivo

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