Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis

Wang, Taide; Tomas, Doris; Perera, Nirma D.; Cuic, Brittany; Luikinga, Sophia J; Viden, Aida; Barton, Samantha K.; McLean, Catriona; Samson, André L.; Southon, Adam; Bush, Ashley I.; Murphy, James M.; Turner, Bradley J.

doi:10.1038/s41418-021-00910-z

Cited by 81 publications

(78 citation statements)

References 61 publications

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“…Numerous reports implicate ferroptosis in a variety of neurodegenerative diseases, including Huntington's disease (HD), Alz-heimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS) (Stockwell et al, 2017; Figure 3). Recent data extend these findings: GPX4 is depleted in post-mortem spinal cords of ALS patients and mouse models; GPX4 overexpression extends survival and delays disease onset in the G93A SOD1 model (Chen et al, 2021c;Wang et al, 2021b); and a pre-clinically and clinically effective treatment for ALS, Cu II (atsm), inhibits ferroptosis (Southon et al, 2020).…”

Section: Neurodegenerationmentioning

confidence: 74%

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

Stockwell

2022

Cell

1,138

772

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Section: Neurodegenerationmentioning

confidence: 74%

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

Stockwell

2022

Cell

1,138

772

View full text Add to dashboard Cite

“…SOD1 mutation also activates hypochlorous acid (HOCl)-myeloperoxidase (MPO) pathway, accelerating ROS accumulation and inhibiting GPX4 expression and thus leading to irreversible lipid peroxidation ( Peng et al, 2022 ). Similar to SOD1 transgenic mice, other ALS animal models including TDP-43 and C9orf72 transgenic mice show GPX4 depletion and dysregulation of glutathione synthesis and iron-binding proteins as well ( Wang et al, 2021 ). The in vivo studies have been corroborated by in vitro ALS model.…”

Section: Emerging Links Of Ferroptosis To Neurodegenerative Diseasesmentioning

confidence: 99%

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Sun

Xia

Basnet

et al. 2022

Front. Aging Neurosci.

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Neurodegenerative diseases are a diverse class of diseases attributed to chronic progressive neuronal degeneration and synaptic loss in the brain and/or spinal cord, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. The pathogenesis of neurodegenerative diseases is complex and diverse, often involving mitochondrial dysfunction, neuroinflammation, and epigenetic changes. However, the pathogenesis of neurodegenerative diseases has not been fully elucidated. Recently, accumulating evidence revealed that ferroptosis, a newly discovered iron-dependent and lipid peroxidation-driven type of programmed cell death, provides another explanation for the occurrence and progression of neurodegenerative diseases. Here, we provide an overview of the process and regulation mechanisms of ferroptosis, and summarize current research progresses that support the contribution of ferroptosis to the pathogenesis of neurodegenerative diseases. A comprehensive understanding of the emerging roles of ferroptosis in neurodegenerative diseases will shed light on the development of novel therapeutic technologies and strategies for slowing down the progression of these diseases.

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“…Ferroptosis is a newly defined cell death pathway that plays an important role in cancer therapy ( 40 ), neuron degeneration diseases ( 41 ), and chemotherapy-induced cardiomyopathy ( 21 ). Ferroptosis is characterized by lipid peroxidation and consequently membrane impairment, which ultimately leads to cell death ( 24 , 29 ).…”

Section: Discussionmentioning

confidence: 99%

GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

Liu

Wen

et al. 2022

Front. Cardiovasc. Med.

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Changes in modern lifestyle provoke a series of metabolic stresses such as hyperlipidemia. Excessive free fatty acids induce cardiomyocyte metabolic reprogramming and rearrangement of the lipid content of cardiomyocyte and promote oxidative stress. As a newly defined lipid peroxidation-related cell death pathway, the role of ferroptosis in metabolic stress-induced cardiomyocyte injury is poorly revealed. Our work indicates that GSK-J4, a histone lysine demethylase 6A/6B dual inhibitor, can alleviate palmitic acid (PA)-induced hypersensitivity to ferroptosis by suppressing H3K27 demethylation. Mechanistically, PA stimulation reduces the H3K27me3 level and hence promotes the expression of ACSL4, a key lipid modulator of ferroptosis. GSK-J4 pretreatment significantly preserves the H3K27me3 level and reduces the ACSL4 level. GSK-J4 also reduces reactive oxygen species to alleviate oxidative stress, which further decreases lipid peroxidation. Taken together, our data suggest that cardiomyocyte undergoes epigenetic reprogramming under metabolic challenges, rearranging lipid content, and sensitizing to ferroptosis. GSK-J4 can be a potential drug for treating hyperlipidemia-induced cardiomyocyte injury by targeting epigenetic modulations.

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Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis

Cited by 81 publications

References 61 publications

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

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