Expression of Pink1 with α-synuclein in the dopaminergic neurons of Drosophila leads to increases in both lifespan and healthspan

Todd, Amy M.; Staveley, Brian E.

doi:10.4238/2012.may.21.6

Cited by 45 publications

(36 citation statements)

References 22 publications

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“…Given the role of Parkin in mediating the clearance of dysfunctional mitochondria via mitophagy and a recent report claiming that Pink1 overexpression in dopaminergic neurons can enhance lifespan (50), it is appropriate to speculate on the role of mitochondria in Parkin-mediated lifespan extension. The process of mitophagy appears to be intimately linked to the Parkin-mediated turnover of mitochondrial OM proteins, including the mitochondrial fusion-promoting factor Mfn (17).…”

Section: Discussionmentioning

confidence: 99%

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

Rana

Rera

Walker

2013

Proc. Natl. Acad. Sci. U.S.A.

280

211

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Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Longlived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusionpromoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.energy metabolism | healthspan | mitophagy | neuronal aging | proteostasis A dvanced age is a major risk factor for many neurodegenerative disorders, including both Alzheimer's disease and Parkinson disease (PD), and yet the molecular mechanisms that link aging and neurodegeneration are poorly understood. To understand this connection, it is necessary to identify the molecular events and pathways that integrate aging and neurodegenerative disease. Several lines of evidence suggest that a decline in the ability to prevent and eliminate protein misfolding (1) and impaired mitochondrial function (2) are important factors in the increased risk of disease and death associated with aging. More specifically, although the correlation between neurodegenerative disease and protein aggregation in the brain has long been recognized (3), recent work in the nematode Caenorhabditis elegans (4-6) and the fruit fly Drosophila melanogaster (7) has shown that aging per se is associated with increased aggregation of a large number of proteins. At the same time, a decline in mitochondrial gene expression and/or energetic capacity is a hallmark of aging across diverse species (2, 8), whereas a failure to eliminate dysfunctional mitochondria has been implicated in the pathophysiology of a number of neurodegenerative diseases, including PD (9).The ubiquitin-proteasome system (UPS) is a critical component of the cellular pro...

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Section: Discussionmentioning

confidence: 99%

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

Rana

Rera

Walker

2013

Proc. Natl. Acad. Sci. U.S.A.

280

211

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“…Fly survival was assessed following a standard protocol, as previously described (Todd and Staveley, 2012;M'Angale and Staveley, 2016). Briefly, over 200 flies were monitored per genotype and scored every 2 days for the presence of deceased adults (Staveley et al, 1990).…”

Section: Survival Assaymentioning

confidence: 99%

Inhibition of Atg6 and Pi3K59F autophagy genes in neurons decreases lifespan and locomotor ability in Drosophila melanogaster

M’Angale

Staveley

2016

Genet. Mol. Res.

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ABSTRACT. Autophagy is a cellular mechanism implicated in the pathology of Parkinson's disease. The proteins Atg6 (Beclin 1) and Pi3K59F are involved in autophagosome formation, a key step in the initiation of autophagy. We first used the GMR-Gal4 driver to determine the effect of reducing the expression of the genes encoding these proteins on the developing Drosophila melanogaster eye. Subsequently, we inhibited their expression in D. melanogaster neurons under the direction of a Dopa decarboxylase (Ddc) transgene, and examined the effects on longevity and motor function. Decreased longevity coupled with an age-dependent loss of climbing ability was observed. In addition, we investigated the roles of these genes in the well-studied α-synuclein-induced Drosophila model of Parkinson's disease. In this context, lowered expression of Atg6 or Pi3K59F in Ddc-Gal4-expressing neurons results in decreased longevity and associated age-dependent loss of locomotor ability. Inhibition of Atg6 or Pi3K59F together with overexpression of the sole pro-survival Bcl-2 Drosophila homolog Buffy in Ddc-Gal4-expressing neurons resulted in further decrease in the survival and climbing ability of Atg6-RNAi flies, whereas these measures were ameliorated in Pi3K59F-RNAi flies.

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“…Several crosses of each genotype were performed and a cohort of male flies were collected upon eclosion (Todd and Staveley, 2012;M'Angale and Staveley, 2016d). For each genotype, at least 200 flies were aged and scored every 2 days for the presence of deceased adults (Staveley et al, 1990).…”

Section: Survival Assaymentioning

confidence: 99%

Knockdown of the putative Lifeguard homologue CG3814 in neurons of Drosophila melanogaster

M’Angale

Staveley

2016

Genet. Mol. Res.

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ABSTRACT.Lifeguard is an integral transmembrane protein that modulates FasL-mediated apoptosis by interfering with the activation of caspase 8. It is evolutionarily conserved, with homologues present in plants, nematodes, zebra fish, frog, chicken, mouse, monkey, and human. The Lifeguard homologue in Drosophila, CG3814, contains the Bax inhibitor-1 family motif of unknown function. Downregulation of Lifeguard disrupts cellular homeostasis and disease by sensitizing neurons to FasL-mediated apoptosis. We used bioinformatic analyses to identify CG3814, a putative homologue of Lifeguard, and knocked down CG3814/LFG expression under the control of the Dopa decarboxylase (Ddc-Gal4) transgene in Drosophila melanogaster neurons to investigate whether it possesses neuroprotective activity. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons resulted in a shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with the degeneration and loss of dopaminergic neurons. Lifeguard interacts with anti-apoptotic Bcl-2 proteins and possibly pro-apoptotic proteins to exert its neuroprotective function. The co-expression of Buffy, the sole anti-apoptotic Bcl-2 gene family member in Drosophila, and CG3814/LFG by stable inducible RNA interference, suppresses the shortened lifespan and the premature agedependent loss in climbing ability. Suppression of CG3814/LFG in the Drosophila eye reduces the number of ommatidia and increases disruption of the ommatidial array. Overexpression of Buffy, along with the knockdown of CG3814/LFG, counteracts the eye phenotypes. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons in Drosophila diminishes its neuroprotective ability and results in a shortened lifespan and loss of climbing ability, phenotypes that are improved upon overexpression of the pro-survival Buffy.

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Expression of Pink1 with α-synuclein in the dopaminergic neurons of Drosophila leads to increases in both lifespan and healthspan

Cited by 45 publications

References 22 publications

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

Inhibition of Atg6 and Pi3K59F autophagy genes in neurons decreases lifespan and locomotor ability in Drosophila melanogaster

Knockdown of the putative Lifeguard homologue CG3814 in neurons of Drosophila melanogaster

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