The neurotoxicity of iron, copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms

Lan, Aiping; Chen, Jun; Chai, Zhifang; Hu, Yadong

doi:10.1007/s10534-016-9942-4

Cited by 75 publications

(48 citation statements)

References 166 publications

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“…Iron is an essential element for cell physiology, participating in a wide variety of cellular processes [40]. However, iron is a potential producer of ROS, and iron overload may promote cell damage by hydroxyl radical formation which leads to protein/lipid oxidation and nucleic acid damage [41,42]. Typically, Perls' staining of PKAN brain tissue shows a widespread perivascular deposition of iron largely confined to the globus pallidus [43].…”

Section: Previous Work Have Demonstrated That Pkan Induced Neurons Bmentioning

confidence: 99%

Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation

et al. 2018

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Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. The most prevalent form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN) associated with mutations in the gene of pantothenate kinase 2 (PANK2), which is essential for coenzyme A (CoA) synthesis. There is no cure for NBIA nor is there a standard course of treatment. In the current work, we describe that fibroblasts derived from patients harbouring PANK2 mutations can reproduce many of the cellular pathological alterations found in the disease, such as intracellular iron and lipofuscin accumulation, increased oxidative stress, and mitochondrial dysfunction. Furthermore, mutant fibroblasts showed a characteristic senescent morphology. Treatment with pantothenate, the PANK2 enzyme substrate, was able to correct all pathological alterations in responder mutant fibroblasts with residual PANK2 enzyme expression. However, pantothenate had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of pantothenate in particular mutations was also confirmed in induced neurons obtained by direct reprograming of mutant fibroblasts. Our results suggest that pantothenate treatment can stabilize the expression levels of PANK2 in selected mutations. These results encourage us to propose our screening model as a quick and easy way to detect pantothenate-responder patients with PANK2 mutations. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of pantothenate.

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Section: Previous Work Have Demonstrated That Pkan Induced Neurons Bmentioning

confidence: 99%

Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation

et al. 2018

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“…Although PD has been extensively researched since its discovery by James Parkinson in 1817, the exact etiology and pathogenesis that underlie dopaminergic cell death are still unclear [11]. However, numerous epidemiological studies revealed that there is a strong association between sporadic PD which represents more than 90% of PD cases and environmental factors such as environmental toxins, pesticides and heavy metals [9]. Besides their colluding with the genetic agents, environmental factors have been demonstrated to cause nigrostriatal cell death through interfering with mitochondrial dysfunction, inducing oxidative stress and modifying proteasomal function [19].…”

Section: Introductionmentioning

confidence: 99%

Neurotoxic effects of domoic acid on dopaminergic neurons in primary mesencephalic cell culture

Radad¹,

Al‐Shraim²,

Al-Emam³

et al. 2018

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Introduction: Domoic acid is a potent marine neurotoxin produced by certain species of the diatom genus Pseudonitzschia. To our knowledge, there are no studies that have investigated neurotoxic effects of domoic acid on dopaminergic neurons. Accordingly, the present study was carried out to investigate the potential neurotoxic effects of domoic acid on dopaminergic neurons in primary mesencephalic cell culture. Material and methods: Cultures prepared from embryonic mouse mesencephala (total of 250 embryos) were treated with different concentrations of domoic acid (0.1, 1, 10, 100 µM) on the 10 th DIV for 48 h. On the 12 th DIV, culture media were used for measurement of lactate dehydrogenase and cultured cells were subjected to immunostaining for tyrosine hydroxylase, neuronal nuclear antigen and glial fibrillary acidic protein, and fluorescence staining using H 2 DCFDA, JC-1 and DAPI stains. Moreover, roles of AMPA/KA and NMDA receptors in domoic acid neurotoxicity were also investigated. Results: Domoic acid significantly decreased the number of dopaminergic neurons, decreased the expression of neuronal nuclear antigen and slightly affected astrocyte populations, and increased the release of lactate dehydrogenase into the culture media. AMPA/KA receptor antagonist NBQX but not NMDA receptor antagonist MK-801 significantly inhibited the neurotoxic effect of domoic acid on dopaminergic neurons. H 2 DCFDA, JC-1 and DAPI fluorescence staining, respectively, revealed that DomA slightly raised ROS production, and significantly decreased mitochondrial membrane potential and increased apoptotic cell death of cultured cells. Conclusion: The current study presents for the first time the neurotoxic effects of domoic acid on dopaminergic neurons and this effect appears to be attributed to activation of AMPA/KA receptors on dopaminergic neurons.

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“…Studies indicate that Cu accumulates in specific brain regions of aged subjects (Braidy et al., ; Fu, Jiang, & Zheng, ; Pushkar et al., ; Singh et al., ; Wang, Becker, et al., ; Zatta et al., ). In neurodegenerative diseases, long‐term Cu dyshomeostasis plays a role in oxidative damage, and redox‐active Cu accelerates formation of toxic oligomers associated with some neurodegenerative factors (e.g., Amyloid β, alpha synuclein) (Ahuja, Dev, Tanwar, Selwal, & Tyagi, ; Dell'Acqua et al., ; Greenough et al., ; Kawahara et al., ; Lan, Chen, Chai, & Hu, ; Okita et al., ; Squitti, ; Villar‐Pique et al., ). Thus, some circadian abnormalities observed in aged subjects and those with neurological diseases may involve Cu dyshomeostasis, an idea that warrants further study.…”

Section: Discussionmentioning

confidence: 99%

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

Yamada

Prosser

2018

Eur J of Neuroscience

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The mammalian circadian clock in the suprachiasmatic nucleus (SCN) is very robust, able to coordinate our daily physiological and behavioral rhythms with exquisite accuracy. Simultaneously, the SCN clock is highly sensitive to environmental timing cues such as the solar cycle. This duality of resiliency and sensitivity may be sustained in part by a complex intertwining of three cellular oscillators: transcription/translation, metabolic/redox, and membrane excitability. We suggest here that one of the links connecting these oscillators may be forged from copper (Cu). Cellular Cu levels are highly regulated in the brain and peripherally, and Cu affects cellular metabolism, redox state, cell signaling, and transcription. We have shown that both Cu chelation and application induce nighttime phase shifts of the SCN clock in vitro and that these treatments affect glutamate, N‐methyl‐D‐aspartate receptor, and associated signaling processes differently. More recently we found that Cu induces mitogen‐activated protein kinase‐dependent phase shifts, while the mechanisms by which Cu removal induces phase shifts remain unclear. Lastly, we have found that two Cu transporters are expressed in the SCN, and that one of these transporters (ATP7A) exhibits a day/night rhythm. Our results suggest that Cu homeostasis is tightly regulated in the SCN, and that changes in Cu levels may serve as a time cue for the circadian clock. We discuss these findings in light of the existing literature and current models of multiple coupled circadian oscillators in the SCN.

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The neurotoxicity of iron, copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms

Cited by 75 publications

References 166 publications

Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation

Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation

Neurotoxic effects of domoic acid on dopaminergic neurons in primary mesencephalic cell culture

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

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