Epigenetic Regulation of Ferroptosis in Central Nervous System Diseases

Lan, Ting; Sun, Ting; Wei, Chao; Tian, Chen; Yang, Fei; Zhang, Jian-Nan; Li, Qian

doi:10.1007/s12035-023-03267-1

Cited by 15 publications

(4 citation statements)

References 111 publications

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“…S7A ). TRIM24 is involved in transcriptional initiation and shows differential expression in individuals with Parkinson disease [49,50]. Another suggestive locus is TNXB , located in the major histocompatibility complex (MHC) region on chromosome 6, with the lead SNV rs367364 ( P = 7.07 × 10 -7 , β = −0.37, MAF = 0.13, Fig.…”

Section: Resultsmentioning

confidence: 99%

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Wang,

Chang,

Dombroski

et al. 2023

Preprint

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Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. We performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), small insertions/deletions (indels), and structural variants (SVs) in a cohort of 1,718 individuals with PSP and 2,944 control subjects. Analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and also uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. In contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele and the ε4 allele to be protective, a pattern similar to the association pattern observed in age-related macular degeneration (AMD) but the opposite observed for Alzheimer's disease (AD). Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. We also observed seven common SVs associated with PSP on the H1/H2 haplotype region (17q21.31) and in a few other loci: IGH, PCMT1, CYP2A13, and SMCP. Particularly, in the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73x10-3) in PSP. Through WGS, we significantly refine our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

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Section: Resultsmentioning

confidence: 99%

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Wang,

Chang,

Dombroski

et al. 2023

Preprint

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show abstract

“…154 Given the complex interactions among iron metabolism, oxidative stress, organelle dysfunction, and neuroinflammation at different disease stages, it is unlikely that targeting an individual component of the ferroptosis pathway will provide substantial clinical benefit. Novel therapies, such as epigenetic approaches 11 or multitargeting drugs with iron-chelating, antioxidant, antiferroptotic, and anti-inflammatory properties may provide potential alternatives.…”

Section: Perspectivementioning

confidence: 99%

“…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.…”

mentioning

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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“… 8 , 14 – 16 Moreover, emerging evidence has revealed the roles of epigenetic modifications and PTMs in the regulation of ferroptosis in NSDs, CVDs, liver diseases, lung diseases, and kidney diseases. 17 …”

Section: Introductionmentioning

confidence: 99%

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Wang,

Hu,

et al. 2023

Sig Transduct Target Ther

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Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications and posttranslational modifications (PTMs) promote anticancer drug resistance, cancer progression, and metastasis. Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases (NSDs), cardiovascular diseases (CVDs), liver diseases, lung diseases, and kidney diseases. In this review, we first summarize the core molecular mechanisms of ferroptosis. Then, the roles of epigenetic processes, including histone PTMs, DNA methylation, and noncoding RNA regulation and PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, and ADP-ribosylation, are concisely discussed. The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases, including cancers, NSD, CVDs, liver diseases, lung diseases, and kidney diseases, as well as the application of epigenetic and PTM modulators in the therapy of these diseases, are then discussed in detail. Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases. In addition, these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

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Epigenetic Regulation of Ferroptosis in Central Nervous System Diseases

Cited by 15 publications

References 111 publications

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

What Is the Role of Ferroptosis in Neurodegeneration?

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

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