Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition

Mahoney-Sánchez, Laura; Bouchaoui, Hind; Boussaad, Ibrahim; Jonneaux, Aurélie; Timmerman, Kelly; Berdeaux, Olivier; Ayton, Scott; Krüger, Rejko; Duce, James A.; Devos, David; Devedjian, Jean-Christophe

doi:10.1016/j.celrep.2022.111231

Cited by 38 publications

(31 citation statements)

References 69 publications

(119 reference statements)

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“…126 In human dopaminergic neuron models, endogenous levels of α-synuclein can affect the availability of ether-linked phospholipids required for ferroptosis. 127,128 Aggregated α-synuclein also induces the production of ROS and formation of lipid peroxidation products, which in turn, promote α-synuclein aggregation, thus perpetuating the pathogenic cycle. 129,130 Misfolded α-synuclein also activates microglia, which release interleukin-6 that induces changes in the neuronal transcriptome promoting iron uptake and decreases iron export.…”

Section: Role Of Ferroptosis In Neurologic Diseasementioning

confidence: 99%

What Is the Role of Ferroptosis in Neurodegeneration?

Benarroch

2023

Neurology

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Ferroptosis is a unique form of programmed cell death pathway that is mechanistically different from necrosis, apoptosis, or autophagy.1 Ferroptosis is induced by reactive oxygen species (ROS) originating from multiple sources, especially accumulation of free intracellular divalent iron (Fe2+), leading to peroxidation of polyunsaturated fatty acids (PUFAs) and resulting in membrane damage (Figure). One major trigger of ferroptosis is decreased availability of intracellular antioxidant enzymes, particularly glutathione peroxidases (GPXs).1-7 Because of its high lipid concentration and oxygen consumption rate, the nervous tissue is extremely vulnerable to oxidative damage and ferroptosis. With aging, iron accumulates in the brain, which predisposes to and exacerbates these processes.8 Iron promotes ferroptosis both directly and as a cofactor required for the activity of enzymes mediating redox reactions and lipid peroxidation.9,10 Epigenetic regulation can determine cell sensitivity to ferroptosis by affecting intracellular iron levels, oxidative stress, and lipid metabolism.11 Ferroptosis affects all cell types in the nervous system, including neurons, glial cells, and pericytes.12 Microglia are the primary iron-accumulating cells in disease.13,14 Recent evidence indicates that iron-laden microglia have a critical role in ferroptosis associated with neurodegeneration.15 Studies in vitro, in experimental disease models, and in human brain tissue indicate that iron accumulation, oxidative stress, and lipid peroxidation are major disease mechanisms in a wide range of neurologic disorders. These studies also suggest that the different components of the ferroptosis pathway are potential targets for therapeutic intervention. The mechanisms of ferroptosis and its role in neurologic disorders have been the subject of several recent comprehensive reviews.7,8,16-21 Some of these concepts pertinent to neurodegeneration will be emphasized in this study.

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Section: Role Of Ferroptosis In Neurologic Diseasementioning

confidence: 99%

What Is the Role of Ferroptosis in Neurodegeneration?

Benarroch

2023

Neurology

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“…In addition, low activity of the GPX4 and GSH systems has been shown to be associated with ferroptosis in motor neurodegeneration. The level of endogenous α-synuclein can determine the sensitivity of dopaminergic neurons to ferroptosis, by regulating the composition of ether phospholipid membrane [ 127 ]. In AD, ferroptosis may induce iron homeostasis disorder by downregulating FPN, and excess iron exacerbates oxidative damage and cognitive defects [ 128 ].…”

Section: Ferroptosis and Inflammatory Diseasementioning

confidence: 99%

Molecular mechanisms of ferroptosis and relevance to inflammation

Deng

Guo

et al. 2022

Inflamm. Res.

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Introduction Inflammation is a defensive response of the organism to irritation which is manifested by redness, swelling, heat, pain and dysfunction. The inflammatory response underlies the role of various diseases. Ferroptosis, a unique modality of cell death, driven by iron-dependent lipid peroxidation, is regulated by multifarious cellular metabolic pathways, including redox homeostasis, iron processing and metabolism of lipids, as well as various signaling pathways associated with diseases. A growing body of evidence suggests that ferroptosis is involved in inflammatory response, and targeting ferroptosis has great prospects in preventing and treating inflammatory diseases. Materials and methods Relevant literatures on ferroptosis, inflammation, inflammatory factors and inflammatory diseases published from January 1, 2010 to now were searched in PubMed database. Conclusion In this review, we summarize the regulatory mechanisms associated with ferroptosis, discuss the interaction between ferroptosis and inflammation, the role of mitochondria in inflammatory ferroptosis, and the role of targeting ferroptosis in inflammatory diseases. As more and more studies have confirmed the relationship between ferroptosis and inflammation in a wide range of organ damage and degeneration, drug induction and inhibition of ferroptosis has great potential in the treatment of immune and inflammatory diseases.

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“…In patients’ small-molecule-derived neuronal precursor cells with SNCA triplication, elevated α-syn expression increases lipid peroxidation and ferroptosis. Reducing α-syn expression in DA neurons leads to ferroptosis resistance due to a reduction in ether-linked phospholipids, which is required for ferroptosis [ 345 ]. Many genes have been involved in regulating ferroptosis ( Figure 4 ).…”

Section: Ferroptosis In Pdmentioning

confidence: 99%

Pathogenesis of α-Synuclein in Parkinson’s Disease: From a Neuron-Glia Crosstalk Perspective

Wang

et al. 2022

IJMS

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder. The classical behavioral defects of PD patients involve motor symptoms such as bradykinesia, tremor, and rigidity, as well as non-motor symptoms such as anosmia, depression, and cognitive impairment. Pathologically, the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the accumulation of α-synuclein (α-syn)-composed Lewy bodies (LBs) and Lewy neurites (LNs) are key hallmarks. Glia are more than mere bystanders that simply support neurons, they actively contribute to almost every aspect of neuronal development and function; glial dysregulation has been implicated in a series of neurodegenerative diseases including PD. Importantly, amounting evidence has added glial activation and neuroinflammation as new features of PD onset and progression. Thus, gaining a better understanding of glia, especially neuron-glia crosstalk, will not only provide insight into brain physiology events but also advance our knowledge of PD pathologies. This review addresses the current understanding of α-syn pathogenesis in PD, with a focus on neuron-glia crosstalk. Particularly, the transmission of α-syn between neurons and glia, α-syn-induced glial activation, and feedbacks of glial activation on DA neuron degeneration are thoroughly discussed. In addition, α-syn aggregation, iron deposition, and glial activation in regulating DA neuron ferroptosis in PD are covered. Lastly, we summarize the preclinical and clinical therapies, especially targeting glia, in PD treatments.

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Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition

Cited by 38 publications

References 69 publications

What Is the Role of Ferroptosis in Neurodegeneration?

What Is the Role of Ferroptosis in Neurodegeneration?

Molecular mechanisms of ferroptosis and relevance to inflammation

Pathogenesis of α-Synuclein in Parkinson’s Disease: From a Neuron-Glia Crosstalk Perspective

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