Oxidative stress has been strongly associated with Parkinson disease (PD) aetiology. We investigated the effects of blueberry extract (BBE) supplementation on α-synuclein induced phenotypes in a Drosophila melanogast...Oxidative stress has been strongly associated with Parkinson disease (PD) aetiology. We investigated the effects of blueberry extract (BBE) supplementation on α-synuclein induced phenotypes in a Drosophila melanogaster model of PD. Enhanced α-synuclein expression in D. melanogaster dopaminergic (DA) neurons can reduce lifespan and we have performed longevity assays to measure the effects of BBE on D. melanogaster survival. Flies expressing α-synuclein in their DA neurons fed BBE had up to an 8 day, or 15%, greater median lifespan than those fed a standard control diet. In addition, BBE improved α-synuclein-induced developmental defects in the Drosophila eye. Our biometric analyses revealed that individuals fed BBE had less atypical ommatidia as well as an increased number of mechanosensory bristle cells than those fed a control diet. We propose that BBE, rich in naturally occurring antioxidants, promotes the survival of neurons in tissues with increased levels of α-synuclein through a protective cell survival mechanism.展开更多
Parkinson disease pathology often includes the presence of ubiquitin-positive, α-synuclein-enriched inclusions in the remaining neurons. Pink1 (also identified as PARK6) encodes a serinethreonine kinase involved in m...Parkinson disease pathology often includes the presence of ubiquitin-positive, α-synuclein-enriched inclusions in the remaining neurons. Pink1 (also identified as PARK6) encodes a serinethreonine kinase involved in mitochondrial protection that works with parkin to ubiquitinate various proteins, promoting mitophagy. The parkin protein works to tag cystolic proteins for degradation, and previous work in our laboratory has shown the ability of parkin to rescue a Gal4-induced phenotype. To further investigate the role of Pink1 in protection against toxic proteins, we have performed expression studies to determine the effects of increases and decreases in Pink1 on the Gal4-induced phenotype consisting of developmental defects in the Drosophila eye. Our results show that Pink1 is able to rescue the Gal4-induced phenotype, highlighting a protective role for Pink1 against toxic proteins. When expressing low levels of Gal4, reductions in Pink1 or parkin are not able to induce a phenotype. This suggests that Pink1 or parkin may counter Gal4 effects despite reductions, or that the effects of low level Gal4 may be alleviated by an alternative mechanism. Moreover, the Pink1 mechanism of action during differing types of cell stress, including degradation of toxic proteins, warrants further investigation.展开更多
Pink1 has been linked to both autosomal recessive and sporadic forms of Parkinson disease. The Pink1 protein is thought to be involved in mitochondrial protection by interacting with parkin to prevent oxidative damage...Pink1 has been linked to both autosomal recessive and sporadic forms of Parkinson disease. The Pink1 protein is thought to be involved in mitochondrial protection by interacting with parkin to prevent oxidative damage, maintain mitochondrial integrity and regulate mitophagy. Pink1 and parkin have been linked to components of the insulin receptor (INR) pathway, including PTEN, Akt and Foxo, but their effects in the INR pathway have been largely overlooked. To further investigate the roles of Pink1/parkin, we have performed co-expression studies to determine the effects Pink1 and parkin on the Foxo-induced phenotype of developmental defects in the Drosophila eye. We examined directed expression of Pink1, parkin, Pink1 or parkin mutants, and Pink1 or parkin interfering RNAs (RNAi) with the overexpression of Foxo in the developing eye of Drosophila. Our findings show that reduction of Pink1 suppresses the effects of Foxo overexpression, where co-overexpression with Pink1 or parkin increases the severity of the phenotype. This suggests that Pink1 and parkin are able to increase the pro-apoptotic effects of Foxo. Contrary to the view that Pink1 and parkin act exclusively as protective proteins in the cell, it is likely that the Pink1/parkin pathway is involved in aspects of cell fate decisions other than degrading toxic proteins and maintaining mitochondrial integrity.展开更多
Symptoms of Parkinson Disease (PD), the second most common neurodegenerative disease, emerge due to degeneration of dopaminergic neurons. Recently, a genome wide study revealed a role for a foxo transcription factor i...Symptoms of Parkinson Disease (PD), the second most common neurodegenerative disease, emerge due to degeneration of dopaminergic neurons. Recently, a genome wide study revealed a role for a foxo transcription factor in PD. In the model organism Drosophila melanogaster, we have attempted 1) to inhibit the sole Drosophila homologue of foxo through the directed expression of a stable inducible RNAi transgene and 2) to indirectly increase foxo transcription activity through the inhibition of the kinase minibrain (mnb), a foxo transcriptional inhibitor. To evaluate the lifetime consequences upon the flies, longevity assays and locomotion over time assays were conducted. The inhibition of foxo by foxo-RNAi decreases life span significantly when expressed under the control of Tyrosine Hydroxylase-Gal4 (TH-Gal4). The targeted expression of mnb-RNAi, in the dopaminergic neurons, with an expected loss of suppression of foxo transcriptional activity, results in a significant loss of climbing ability. Thus alteration of foxo activity, both by RNA-inhibition and by down-regulation of an inhibitor of foxo, minibrain, produces novel Drosophila models of Parkinson Disease.展开更多
文摘Oxidative stress has been strongly associated with Parkinson disease (PD) aetiology. We investigated the effects of blueberry extract (BBE) supplementation on α-synuclein induced phenotypes in a Drosophila melanogaster model of PD. Enhanced α-synuclein expression in D. melanogaster dopaminergic (DA) neurons can reduce lifespan and we have performed longevity assays to measure the effects of BBE on D. melanogaster survival. Flies expressing α-synuclein in their DA neurons fed BBE had up to an 8 day, or 15%, greater median lifespan than those fed a standard control diet. In addition, BBE improved α-synuclein-induced developmental defects in the Drosophila eye. Our biometric analyses revealed that individuals fed BBE had less atypical ommatidia as well as an increased number of mechanosensory bristle cells than those fed a control diet. We propose that BBE, rich in naturally occurring antioxidants, promotes the survival of neurons in tissues with increased levels of α-synuclein through a protective cell survival mechanism.
文摘Parkinson disease pathology often includes the presence of ubiquitin-positive, α-synuclein-enriched inclusions in the remaining neurons. Pink1 (also identified as PARK6) encodes a serinethreonine kinase involved in mitochondrial protection that works with parkin to ubiquitinate various proteins, promoting mitophagy. The parkin protein works to tag cystolic proteins for degradation, and previous work in our laboratory has shown the ability of parkin to rescue a Gal4-induced phenotype. To further investigate the role of Pink1 in protection against toxic proteins, we have performed expression studies to determine the effects of increases and decreases in Pink1 on the Gal4-induced phenotype consisting of developmental defects in the Drosophila eye. Our results show that Pink1 is able to rescue the Gal4-induced phenotype, highlighting a protective role for Pink1 against toxic proteins. When expressing low levels of Gal4, reductions in Pink1 or parkin are not able to induce a phenotype. This suggests that Pink1 or parkin may counter Gal4 effects despite reductions, or that the effects of low level Gal4 may be alleviated by an alternative mechanism. Moreover, the Pink1 mechanism of action during differing types of cell stress, including degradation of toxic proteins, warrants further investigation.
文摘Pink1 has been linked to both autosomal recessive and sporadic forms of Parkinson disease. The Pink1 protein is thought to be involved in mitochondrial protection by interacting with parkin to prevent oxidative damage, maintain mitochondrial integrity and regulate mitophagy. Pink1 and parkin have been linked to components of the insulin receptor (INR) pathway, including PTEN, Akt and Foxo, but their effects in the INR pathway have been largely overlooked. To further investigate the roles of Pink1/parkin, we have performed co-expression studies to determine the effects Pink1 and parkin on the Foxo-induced phenotype of developmental defects in the Drosophila eye. We examined directed expression of Pink1, parkin, Pink1 or parkin mutants, and Pink1 or parkin interfering RNAs (RNAi) with the overexpression of Foxo in the developing eye of Drosophila. Our findings show that reduction of Pink1 suppresses the effects of Foxo overexpression, where co-overexpression with Pink1 or parkin increases the severity of the phenotype. This suggests that Pink1 and parkin are able to increase the pro-apoptotic effects of Foxo. Contrary to the view that Pink1 and parkin act exclusively as protective proteins in the cell, it is likely that the Pink1/parkin pathway is involved in aspects of cell fate decisions other than degrading toxic proteins and maintaining mitochondrial integrity.
文摘Symptoms of Parkinson Disease (PD), the second most common neurodegenerative disease, emerge due to degeneration of dopaminergic neurons. Recently, a genome wide study revealed a role for a foxo transcription factor in PD. In the model organism Drosophila melanogaster, we have attempted 1) to inhibit the sole Drosophila homologue of foxo through the directed expression of a stable inducible RNAi transgene and 2) to indirectly increase foxo transcription activity through the inhibition of the kinase minibrain (mnb), a foxo transcriptional inhibitor. To evaluate the lifetime consequences upon the flies, longevity assays and locomotion over time assays were conducted. The inhibition of foxo by foxo-RNAi decreases life span significantly when expressed under the control of Tyrosine Hydroxylase-Gal4 (TH-Gal4). The targeted expression of mnb-RNAi, in the dopaminergic neurons, with an expected loss of suppression of foxo transcriptional activity, results in a significant loss of climbing ability. Thus alteration of foxo activity, both by RNA-inhibition and by down-regulation of an inhibitor of foxo, minibrain, produces novel Drosophila models of Parkinson Disease.
