Expression of zinc-deficient human superoxide dismutase in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction

Bahadorani, Sepehr; Mukai, Spencer T.; Rabie, Jason; Beckman, Joseph S.; Phillips, J. P.; Hilliker, Arthur J.

doi:10.1016/j.neurobiolaging.2013.03.024

Cited by 37 publications

(28 citation statements)

References 42 publications

(63 reference statements)

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“…In agreement with other studies333435363738 our results point to a possible link between SOD1, mitochondrial dysfunction and ALS. Intriguingly, we showed that the over-expression of the wild type hSOD1 also causes mitochondrial alterations.…”

Section: Discussionsupporting

confidence: 93%

Differential effects of phytotherapic preparations in the hSOD1 Drosophila melanogaster model of ALS

Rose

Talani

Catelani

et al. 2017

Sci Rep

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The present study was aimed at characterizing the effects of Withania somnifera (Wse) and Mucuna pruriens (Mpe) on a Drosophila melanogaster model for Amyotrophic Lateral Sclerosis (ALS). In particular, the effects of Wse and Mpe were assessed following feeding the flies selectively overexpressing the wild human copper, zinc-superoxide dismutase (hSOD1-gain-of-function) in Drosophila motoneurons. Although ALS-hSOD1 mutants showed no impairment in life span, with respect to GAL4 controls, the results revealed impairment of climbing behaviour, muscle electrophysiological parameters (latency and amplitude of ePSPs) as well as thoracic ganglia mitochondrial functions. Interestingly, Wse treatment significantly increased lifespan of hSDO1 while Mpe had not effect. Conversely, both Wse and Mpe significantly rescued climbing impairment, and also latency and amplitude of ePSPs as well as failure responses to high frequency DLM stimulation. Finally, mitochondrial alterations were any more present in Wse- but not in Mpe-treated hSOD1 mutants. Hence, given the role of inflammation in the development of ALS, the high translational impact of the model, the known anti-inflammatory properties of these extracts, and the viability of their clinical use, these results suggest that the application of Wse and Mpe might represent a valuable pharmacological strategy to counteract the progression of ALS and related symptoms.

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Section: Discussionsupporting

confidence: 93%

Differential effects of phytotherapic preparations in the hSOD1 Drosophila melanogaster model of ALS

Rose

Talani

Catelani

et al. 2017

Sci Rep

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“…Zinc also contributes to neuronal death in hypoxic-ischemic injury (34,35,(47)(48)(49) by interfering with mitochondrial and metabolic functions (50,51), altering ion fluxes (52), and other mechanisms (53). Abnormalities in zinc homeostasis may be important in chronic neurodegenerative diseases, such as Alzheimer's (54) and amyotrophic lateral sclerosis (55)(56)(57), and have been shown to play a key role in oxidative stress-induced death in neurons and oligodendrocytes (58,59). Given the abundant evidence for the importance of zinc in acute and chronic neurodegeneration, we have investigated its involvement in the death of RGCs following optic nerve injury.…”

Section: Significancementioning

confidence: 99%

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Andereggen

Yuki

et al. 2017

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

123

129

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Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn 2+ ) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn 2+ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn 2+ accumulation in amacrine cell processes involves the Zn 2+ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn 2+ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn 2+ chelation extends for several days after nerve injury. These results show that retinal Zn 2+ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn 2+ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.T he optic nerve has been widely used to investigate the response of CNS neurons to injury because of its accessibility, anatomy, and functional importance. Under normal circumstances, retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate axons after the optic nerve has been damaged and soon undergo cell death, leaving victims of traumatic or ischemic nerve injury or degenerative conditions, such as glaucoma, with permanent visual losses. Optic nerve injury leads to numerous pathological changes in RGCs and reversing some of these changes improves cell survival, although these effects are often transitory and for the most part promote little or no axon regeneration (1-10). Regeneration per se can be induced by intraocular inflammation combined with elevated cAMP (11, 12), counteracting cell-intrinsic (13-15) or cellextrinsic (16, 17) suppressors of axon growth, oncomodulin and other growth factors (18-22), or elevated physiological activity (23,24). Some of these treatments act synergistically and enable a modest number of RGCs to reestablish connections with appropriate target areas in the brain (25-27). However, although these studies show that successful regeneration can occur in principle, most RGCs eventually die after optic nerve injury, and to date only a small fraction of surviving RGCs have been induced to regenerate axons (27). These observations imply the existence of other major, as yet unknown suppressors of cell survival and regeneration. Our results point to zinc dysregulation as a critical factor.Zinc is essential for many cellular functions. Covalently bound zinc is required for the activity of numerous enzymes and t...

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“…ALS-associated mutations can hinder binding of SOD1protein to zinc ions, resulting in cellular toxicity (Crow et al, 1997;Lyons et al, 1996). Recently, researchers using transgenic Drosophila expressing zinc-deficient hSOD1 obtained evidence supporting a link between mutant SOD1 and mitochondrial dysfunction (Bahadorani et al, 2013). These flies harbored a D83S mutation in a zinc-binding domain of exon 4 that inhibits binding of SOD1 protein to zinc, without affecting binding to its other cofactor, copper.…”

Section: 0 Drosophila Models Of Alsmentioning

confidence: 99%

A fruitful endeavor: Modeling ALS in the fruit fly

Casci

Pandey

2015

Brain Research

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For over a century Drosophila melanogaster, commonly known as the fruit fly, has been instrumental in genetics research and disease modeling. In more recent years, it has been a powerful tool for modeling and studying neurodegenerative diseases, including the devastating and fatal amyotrophic lateral sclerosis (ALS). The success of this model organism in ALS research comes from the availability of tools to manipulate gene/protein expression in a number of desired cell-types, and the subsequent recapitulation of cellular and molecular phenotypic features of the disease. Several Drosophila models have now been developed for studying the roles of ALS-associated genes in disease pathogenesis that allowed us to understand the molecular pathways that lead to motor neuron degeneration in ALS patients. Our primary goal in this review is to highlight the lessons we have learned using Drosophila models pertaining to ALS research.

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Expression of zinc-deficient human superoxide dismutase in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction

Cited by 37 publications

References 42 publications

Differential effects of phytotherapic preparations in the hSOD1 Drosophila melanogaster model of ALS

Differential effects of phytotherapic preparations in the hSOD1 Drosophila melanogaster model of ALS

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

A fruitful endeavor: Modeling ALS in the fruit fly

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