Lipid peroxidation is essential for phospholipase C activity and IP3 related calcium signal

Domijan, Ana-Marija; Kovač, Stjepana; Abramov, Andrey Y.

doi:10.1242/jcs.138370

Cited by 51 publications

(36 citation statements)

References 28 publications

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“…ROS is normally produced in healthy cells during metabolic processes and known to have an important role as signaling molecules (25, 51). Oxidative stress is defined as a misbalance in cell redox reactions, resulting in the increase of ROS and decreased antioxidant defense systems.…”

Section: Resultsmentioning

confidence: 99%

Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

Deas

Cremades

Angelova

et al. 2016

Antioxidants & Redox Signaling

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285

269

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Aims: Protein aggregation and oxidative stress are both key pathogenic processes in Parkinson's disease, although the mechanism by which misfolded proteins induce oxidative stress and neuronal death remains unknown. In this study, we describe how aggregation of alpha-synuclein (α-S) from its monomeric form to its soluble oligomeric state results in aberrant free radical production and neuronal toxicity. Results: We first demonstrate excessive free radical production in a human induced pluripotent stem-derived α-S triplication model at basal levels and on application of picomolar doses of β-sheet-rich α-S oligomers. We probed the effects of different structural species of α-S in wild-type rat neuronal cultures and show that both oligomeric and fibrillar forms of α-S are capable of generating free radical production, but that only the oligomeric form results in reduction of endogenous glutathione and subsequent neuronal toxicity. We dissected the mechanism of oligomer-induced free radical production and found that it was interestingly independent of several known cellular enzymatic sources. Innovation: The oligomer-induced reactive oxygen species (ROS) production was entirely dependent on the presence of free metal ions as addition of metal chelators was able to block oligomer-induced ROS production and prevent oligomer-induced neuronal death. Conclusion: Our findings further support the causative role of soluble amyloid oligomers in triggering neurodegeneration and shed light into the mechanisms by which these species cause neuronal damage, which, we show here, can be amenable to modulation through the use of metal chelation. Antioxid. Redox Signal. 24, 376–391.

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Section: Resultsmentioning

confidence: 99%

Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

Deas

Cremades

Angelova

et al. 2016

Antioxidants & Redox Signaling

Self Cite

285

269

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“…49, 50 Lipid peroxidation also activates phospholipase C (PLC) in the rat brain homogenate, while reactive oxygen species scavengers block PLC activity and downstream signaling. 51 Lipid hydroperoxides and their derivatives change the physical properties of cell membranes by altering phospholipid structure, orientation and dynamics. 52, 53 Perturbation of red cell membrane by t -butyl hydroperoxide alters membrane phospholipid composition and permeability function.…”

Section: Discussionmentioning

confidence: 99%

Impaired embryonic development in glucose-6-phosphate dehydrogenase-deficient Caenorhabditis elegans due to abnormal redox homeostasis induced activation of calcium-independent phospholipase and alteration of glycerophospholipid metabolism

et al. 2017

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a commonly pervasive inherited disease in many parts of the world. The complete lack of G6PD activity in a mouse model causes embryonic lethality. The G6PD-deficient Caenorhabditis elegans model also shows embryonic death as indicated by a severe hatching defect. Although increased oxidative stress has been implicated in both cases as the underlying cause, the exact mechanism has not been clearly delineated. In this study with C. elegans, membrane-associated defects, including enhanced permeability, defective polarity and cytokinesis, were found in G6PD-deficient embryos. The membrane-associated abnormalities were accompanied by impaired eggshell structure as evidenced by a transmission electron microscopic study. Such loss of membrane structural integrity was associated with abnormal lipid composition as lipidomic analysis revealed that lysoglycerophospholipids were significantly increased in G6PD-deficient embryos. Abnormal glycerophospholipid metabolism leading to defective embryonic development could be attributed to the increased activity of calcium-independent phospholipase A2 (iPLA) in G6PD-deficient embryos. This notion is further supported by the fact that the suppression of multiple iPLAs by genetic manipulation partially rescued the embryonic defects in G6PD-deficient embryos. In addition, G6PD deficiency induced disruption of redox balance as manifested by diminished NADPH and elevated lipid peroxidation in embryos. Taken together, disrupted lipid metabolism due to abnormal redox homeostasis is a major factor contributing to abnormal embryonic development in G6PD-deficient C. elegans.

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“…; Domijan et al . ), but overproduction of ROS may lead to oxidative damage to DNA, proteins and/or to lipid membranes. The extent of tissue damage through oxidation depends on the tissue composition and on the ability of the intracellular antioxidant system to restore ROS production to basal levels.…”

Section: Methodsmentioning

confidence: 99%

Lipid peroxidation is essential for α‐synuclein‐induced cell death

Angelova

Horrocks

Klenerman

et al. 2015

Journal of Neurochemistry

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119

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Parkinson’s disease is the second most common neurodegenerative disease and its pathogenesis is closely associated with oxidative stress. Deposition of aggregated α-synuclein (α-Syn) occurs in familial and sporadic forms of Parkinson’s disease. Here, we studied the effect of oligomeric α-Syn on one of the major markers of oxidative stress, lipid peroxidation, in primary co-cultures of neurons and astrocytes. We found that oligomeric but not monomeric α-Syn significantly increases the rate of production of reactive oxygen species, subsequently inducing lipid peroxidation in both neurons and astrocytes. Pre-incubation of cells with isotope-reinforced polyunsaturated fatty acids (D-PUFAs) completely prevented the effect of oligomeric α-Syn on lipid peroxidation. Inhibition of lipid peroxidation with D-PUFAs further protected cells from cell death induced by oligomeric α-Syn. Thus, lipid peroxidation induced by misfolding of α-Syn may play an important role in the cellular mechanism of neuronal cell loss in Parkinson’s disease.

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Lipid peroxidation is essential for phospholipase C activity and IP3 related calcium signal

Cited by 51 publications

References 28 publications

Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

Impaired embryonic development in glucose-6-phosphate dehydrogenase-deficient Caenorhabditis elegans due to abnormal redox homeostasis induced activation of calcium-independent phospholipase and alteration of glycerophospholipid metabolism

Lipid peroxidation is essential for α‐synuclein‐induced cell death

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