The HtrA2 Drosophila model of Parkinson’s disease is suppressed by the pro-survival Bcl-2 Buffy

Genome ◽  
2017 ◽  
Vol 60 (1) ◽  
pp. 1-7 ◽  
Author(s):  
P. Githure M’Angale ◽  
Brian E. Staveley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drosophila Melanogaster ◽  
High Temperature ◽  
Dopaminergic Neurons ◽  
Inhibitors Of Apoptosis ◽  
Drosophila Model ◽  
Age Dependent ◽  
Climbing Ability ◽  
Locomotor Ability

Mutations in High temperature requirement A2 (HtrA2), also designated PARK13, which lead to the loss of its protease activity, have been associated with Parkinson’s disease (PD). HtrA2 is a mitochondrial protease that translocates to the cytosol upon the initiation of apoptosis where it participates in the abrogation of inhibitors of apoptosis (IAP) inhibition of caspases. Here, we demonstrate that the loss of the HtrA2 function in the dopaminergic neurons of Drosophila melanogaster results in PD-like phenotypes, and we attempt to restore the age-dependent loss in locomotor ability by co-expressing the sole pro-survival Bcl-2 homologue Buffy. The inhibition of HtrA2 in the dopaminergic neurons of Drosophila resulted in shortened lifespan and impaired climbing ability, and the overexpression of Buffy rescued the reduction in lifespan and the age-dependent loss of locomotor ability. In supportive experiments, the inhibition of HtrA2 in the Drosophila eye results in eye defects, marked by reduction in ommatidia number and increased disruption of the ommatidial array; phenotypes that are suppressed by the overexpression of Buffy.

scholarly journals ­Bcl-2 homologue debcl enhances α-synuclein-induced phenotypes in Drosophila

2016 ◽  
Author(s):  
Peter G M'Angale ◽  
Brian E Staveley
Keyword(s):  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Degeneration ◽  
Altered Expression ◽  
Drosophila Model ◽  
Age Dependent ◽  
Climbing Ability ◽  
The Common ◽  
Locomotor Ability

Background Parkinson disease (PD) is a debilitating movement disorder that afflicts 1 to 2% of the population over 50 years of age. The common hallmark for both sporadic and familial forms of PD is mitochondrial dysfunction. Mammals have at least twenty proapoptotic and antiapoptotic Bcl-2 family members, in contrast, only two Bcl-2 family genes have been identified in Drosophila melanogaster, the proapoptotic mitochondrial localized debcl and the antiapoptotic Buffy. The expression of α-synuclein, the first gene identified to contribute to inherited forms of PD, in the dopaminergic neurons (DA) of flies has provided a robust and well-studied Drosophila model of PD complete with the loss of neurons and accompanying motor defects. The altered expression of debcl in the DA neurons and neuron-rich eye and along with the expression of α-synuclein offers an opportunity to highlight the role of debcl in mitochondrial-dependent neuronal degeneration and death. Results The directed overexpression of debcl using the Ddc-Gal4 transgene in the dopaminergic neurons of Drosophila resulted in flies with severely decreased survival and a premature age-dependent loss in climbing ability. The inhibition of debcl resulted in enhanced survival and improved climbing ability whereas the overexpression of debcl in the α-synuclein-induced Drosophila model of PD resulted in more severe phenotypes. In addition, the co-expression of debcl along with Buffy partially counteracts the debcl-induced phenotypes, to improve the lifespan and the associated loss of locomotor ability observed. In complementary experiments, the overexpression of debcl along with the expression of α-synuclein in the eye, enhanced the eye ablation that results from the overexpression of debcl. The co-expression of Buffy along with debcl overexpression results in the rescue of the moderate developmental eye defects. The co-expression of Buffy along with inhibition of debcl partially restores the eye to a roughened eye phenotype. Discussion The overexpression of debcl in DA neurons produces flies with shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with models of PD in Drosophila. The co-expression of debcl along with α-synuclein enhanced the Parkinson disease-like phenotypes. The co-expression of debcl along with Buffy suppresses these phenotypes. Complementary experiments in the Drosophila eye show similar trends during development. Taken all together these results suggest a role for debcl in neurodegenerative disorders.

Pink1 suppresses α-synuclein-induced phenotypes in a Drosophila model of Parkinson’s disease

Genome ◽  
2008 ◽  
Vol 51 (12) ◽  
pp. 1040-1046 ◽  
Author(s):  
Amy M. Todd ◽  
Brian E. Staveley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Autosomal Recessive ◽  
Developmental Defects ◽  
Histological Studies ◽  
Progressive Loss ◽  
Drosophila Model ◽  
Climbing Ability ◽  
Protein Toxicity

Parkinson’s disease (PD) is the most prevalent human neurodegenerative movement disorder and is characterized by a selective and progressive loss of the dopaminergic neurons. Mutations in the genes parkin and PTEN-induced putative kinase 1 (PINK1) result in autosomal recessive forms of PD. It has been suggested that parkin and Pink1 function in the same pathway in Drosophila , with Pink1 acting upstream of parkin. Previous work in our laboratory has shown the ability of parkin to rescue an α-synuclein-induced PD-like phenotype in Drosophila. To investigate the ability of Pink1 to protect against α-synuclein-induced toxicity, we have performed longevity, mobility, and histological studies to determine whether Drosophila Pink1 can rescue the α-synuclein phenotypes. We have found that overexpression of Pink1 results in the rescue of the α-synuclein-induced phenotype of premature loss of climbing ability, suppression of degeneration of the ommatidial array, and the suppression of α-synuclein-induced developmental defects in the Drosophila eye. These results mark the first demonstration of Pink1 counteracting PD phenotypes in a protein toxicity animal model, and they show that Pink1 is able to impart protection against potentially harmful proteins such as α-synuclein that would otherwise result in cellular stress.

scholarly journals Bcl-2homologueDebclenhancesα-synuclein-induced phenotypes inDrosophila

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2461 ◽  
Author(s):  
P. Githure M’Angale ◽  
Brian E. Staveley
Keyword(s):  
Neurodegenerative Disorders ◽  
Dopaminergic Neurons ◽  
Neuronal Degeneration ◽  
Altered Expression ◽  
Drosophila Model ◽  
Age Dependent ◽  
Climbing Ability ◽  
The Common ◽  
Locomotor Ability

BackgroundParkinson disease (PD) is a debilitating movement disorder that afflicts 1–2% of the population over 50 years of age. The common hallmark for both sporadic and familial forms of PD is mitochondrial dysfunction. Mammals have at least twenty proapoptotic and antiapoptoticBcl-2family members, in contrast, only twoBcl-2family genes have been identified inDrosophila melanogaster, the proapoptotic mitochondrial localizedDebcland the antiapoptoticBuffy. The expression of the human transgeneα-synuclein, a gene that is strongly associated with inherited forms of PD, in dopaminergic neurons (DA) of Drosophila, results in loss of neurons and locomotor dysfunction to model PD in flies. The altered expression ofDebclin the DA neurons and neuron-rich eye and along with the expression ofα-synucleinoffers an opportunity to highlight the role ofDebclin mitochondrial-dependent neuronal degeneration and death.ResultsThe directed overexpression ofDebclusing theDdc-Gal4transgene in the DA of Drosophila resulted in flies with severely decreased survival and a premature age-dependent loss in climbing ability. The inhibition ofDebclresulted in enhanced survival and improved climbing ability whereas the overexpression ofDebclin theα-synuclein-induced Drosophila model of PD resulted in more severe phenotypes. In addition, the co-expression ofDebclalong withBuffypartially counteracts theDebcl-induced phenotypes, to improve the lifespan and the associated loss of locomotor ability observed. In complementary experiments, the overexpression ofDebclalong with the expression ofα-synucleinin the eye, enhanced the eye ablation that results from the overexpression ofDebcl. The co-expression ofBuffyalong withDebcloverexpression results in the rescue of the moderate developmental eye defects. The co-expression ofBuffyalong with inhibition ofDebclpartially restores the eye to a roughened eye phenotype.DiscussionThe overexpression ofDebclin DA neurons produces flies with shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with models of PD in Drosophila. The co-expression ofDebclalong withα-synucleinenhanced the PD-like phenotypes. The co-expression ofDebclalong withBuffysuppresses these phenotypes. Complementary experiments in the Drosophila eye show similar trends during development. Taken all together these results suggest a role forDebclin neurodegenerative disorders.

scholarly journals ­Bcl-2 homologue debcl enhances α-synuclein-induced phenotypes in Drosophila

2016 ◽  
Author(s):  
Peter G M'Angale ◽  
Brian E Staveley
Keyword(s):  
Parkinson Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Degeneration ◽  
Altered Expression ◽  
Drosophila Model ◽  
Age Dependent ◽  
Climbing Ability ◽  
The Common ◽  
Locomotor Ability

Background Parkinson disease (PD) is a debilitating movement disorder that afflicts 1 to 2% of the population over 50 years of age. The common hallmark for both sporadic and familial forms of PD is mitochondrial dysfunction. Mammals have at least twenty proapoptotic and antiapoptotic Bcl-2 family members, in contrast, only two Bcl-2 family genes have been identified in Drosophila melanogaster, the proapoptotic mitochondrial localized debcl and the antiapoptotic Buffy. The expression of α-synuclein, the first gene identified to contribute to inherited forms of PD, in the dopaminergic neurons (DA) of flies has provided a robust and well-studied Drosophila model of PD complete with the loss of neurons and accompanying motor defects. The altered expression of debcl in the DA neurons and neuron-rich eye and along with the expression of α-synuclein offers an opportunity to highlight the role of debcl in mitochondrial-dependent neuronal degeneration and death. Results The directed overexpression of debcl using the Ddc-Gal4 transgene in the dopaminergic neurons of Drosophila resulted in flies with severely decreased survival and a premature age-dependent loss in climbing ability. The inhibition of debcl resulted in enhanced survival and improved climbing ability whereas the overexpression of debcl in the α-synuclein-induced Drosophila model of PD resulted in more severe phenotypes. In addition, the co-expression of debcl along with Buffy partially counteracts the debcl-induced phenotypes, to improve the lifespan and the associated loss of locomotor ability observed. In complementary experiments, the overexpression of debcl along with the expression of α-synuclein in the eye, enhanced the eye ablation that results from the overexpression of debcl. The co-expression of Buffy along with debcl overexpression results in the rescue of the moderate developmental eye defects. The co-expression of Buffy along with inhibition of debcl partially restores the eye to a roughened eye phenotype. Discussion The overexpression of debcl in DA neurons produces flies with shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with models of PD in Drosophila. The co-expression of debcl along with α-synuclein enhanced the Parkinson disease-like phenotypes. The co-expression of debcl along with Buffy suppresses these phenotypes. Complementary experiments in the Drosophila eye show similar trends during development. Taken all together these results suggest a role for debcl in neurodegenerative disorders.

Mutant α-synuclein-induced degeneration is reduced by parkin in a fly model of Parkinson's disease

Genome ◽  
2006 ◽  
Vol 49 (5) ◽  
pp. 505-510 ◽  
Author(s):  
Annika F.M Haywood ◽  
Brian E Staveley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drosophila Melanogaster ◽  
Retinal Degeneration ◽  
Ubiquitin Ligase ◽  
Dopaminergic Neurons ◽  
Genetic Model ◽  
Protein Functions ◽  
Climbing Ability ◽  
Mutant Forms

Parkinson's disease (PD) patients show a characteristic loss of motor control caused by the degeneration of dopaminergic neurons. Mutations in the genes that encode α-synuclein and parkin have been linked to inherited forms of this disease. The parkin protein functions as a ubiquitin ligase that targets proteins for degradation. Expression of isoforms of human α-synuclein in the Drosophila melanogaster nervous system forms the basis of an excellent genetic model that recapitulates phenotypic and behavioural features of PD. Using this model, we analysed the effect of parkin co-expression on the climbing ability of aging flies, their life span, and their retinal degeneration. We have determined that co-expression of parkin can suppress phenotypes caused by expression of mutant α-synuclein. In the developing eye, parkin reduces retinal degeneration. When co-expressed in the dopaminergic neurons, the ability to climb is extended over time. If conserved in humans, we suggest that upregulation of parkin may prove a method of suppression for PD induced by mutant forms of α-synuclein.Key words: parkin, α-synuclein, Drosophila melanogaster, model of Parkinson's disease.

scholarly journals Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Julia Benkert ◽  
Simon Hess ◽  
Shoumik Roy ◽  
Dayne Beccano-Kelly ◽  
Nicole Wiederspohn ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Viability ◽  
Age Dependent ◽  
Human Ipsc ◽  
Reduced Activity ◽  
Dopaminergic Neuron Loss ◽  
Full Protection

Abstract Degeneration of dopaminergic neurons in the substantia nigra causes the motor symptoms of Parkinson’s disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear. Here we identify Cav2.3 channels as regulators of nigral neuronal viability. Cav2.3 transcripts were more abundant than other voltage-gated Ca2+ channels in mouse nigral neurons and upregulated during aging. Plasmalemmal Cav2.3 protein was higher than in dopaminergic neurons of the ventral tegmental area, which do not degenerate in Parkinson’s disease. Cav2.3 knockout reduced activity-associated nigral somatic Ca2+ signals and Ca2+-dependent after-hyperpolarizations, and afforded full protection from degeneration in vivo in a neurotoxin Parkinson’s mouse model. Cav2.3 deficiency upregulated transcripts for NCS-1, a Ca2+-binding protein implicated in neuroprotection. Conversely, NCS-1 knockout exacerbated nigral neurodegeneration and downregulated Cav2.3. Moreover, NCS-1 levels were reduced in a human iPSC-model of familial Parkinson’s. Thus, Cav2.3 and NCS-1 may constitute potential therapeutic targets for combatting Ca2+-dependent neurodegeneration in Parkinson’s disease.

scholarly journals Editorial for the Special Issue “Animal Models of Parkinson’s Disease and Related Disorders”

2020 ◽  
Vol 21 (12) ◽  
pp. 4250
Author(s):  
Yuzuru Imai
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Motor Dysfunction ◽  
Special Issue ◽  
Midbrain Dopaminergic Neurons ◽  
Age Dependent ◽  
Common Neurodegenerative Disorder

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by age-dependent motor dysfunction and degeneration of the midbrain dopaminergic neurons [...]

Effect of Cabergoline on Cognitive Impairments in Transgenic Drosophila Model of Parkinson’s Disease

2020 ◽  
Vol 17 (10) ◽  
pp. 1261-1269
Author(s):  
Yasir Hasan Siddique ◽  
Rahul ◽  
Mantasha Idrisi ◽  
Mohd. Shahid
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Cognitive Impairments ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Positive Interaction ◽  
Drosophila Model ◽  
Transgenic Drosophila

Background: Parkinson’s disease is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta. Introduction: The effects of alpha synuclein, parkin mutation and pharmacological agents have been studied in the Drosophila model. Methods: The effect of cabergoline was studied on the cognitive impairments exhibited by the transgenic Drosophila expressing human alpha-synuclein in the neurons. The PD flies were allowed to feed on the diet having 0.5, 1 and 1.5 μM of cabergoline. Results and Discussion: The exposure of cabergoline not only showed a dose-dependent significant delay in the cognitive impairments but also prevented the loss of dopaminergic neurons. Molecular docking studies showed the positive interaction between cabergoline and alpha-synuclein. Conclusion: The results suggest a protective effect of cabergoline against the cognitive impairments.

Lemon grass extract alleviates oxidative stress and delayed the loss of climbing ability in transgenic Drosophila model of Parkinson’s disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Yasir Hasan Siddique ◽  
Falaq Naz ◽  
Mantasha I. ◽  
M. Shahid
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Positive Interaction ◽  
Lemon Grass ◽  
Drosophila Model ◽  
Climbing Ability ◽  
Transgenic Drosophila

Background: Parkinson’s Disease (PD) is characterized by the aggregation of α-synuclein, formation of Lewy bodies and the selective loss of dopaminergic neurons of mesencephalic substantia nigra pars compacta (SNC) with the debilitating motor symptoms. Introduction: The available treatment for PD provides symptomatic relief with no control on the progression of the disease. The treatment is also associated with several side effects. As the neurodegeneration in PD is also associated with the oxidative stress, antioxidants from plants could play an important role in reducing the PD symptoms. With this aim we decided to study the effect of Lemon grass extract (LGE) on the transgenic Drosophila model of PD expressing human alpha synuclein in the neurons. Methods: The PD flies allowed were allowed to feed on different doses of LGE established in diet for 24 days and then assayed for climbing ability and oxidative stress markers. The molecular docking study was also performed for citral (the component of the extract) and human α-synuclein. Results and discussion: A dose dependent significant improvement in the climbing ability and reduction in oxidative stress was observed in the PD flies exposed to LGE. In our earlier study on LGE, citral was found to be the main component of the extract by GC-MS analysis. The docking results also support the positive interaction between citral and human α-synuclein. Conclusion: The results suggests that LGE is potemnt in reducing the PD symptoms being mimicked in transgenic Drosophila.

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