Ferroptosis and Its Role in Diverse Brain Diseases

Weiland, Abigail; Wang, Yamei; Wu, Weihua; Lan, Xi; Han, Xiaoning; Li, Qian; Wang, Jian

doi:10.1007/s12035-018-1403-3

Cited by 362 publications

(262 citation statements)

References 164 publications

(233 reference statements)

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“…These lectures and texts generally focused on aggregation and fibrillization alone. However, the current literature is becoming increasingly clear concerning the very important connections between iron and AD, PD, Prion disease, motor neurone disease, and other chronic slowly-progressing neurodegenerative diseases (Biasiotto et al, 2015;Ndayisaba et al, 2019;Weiland et al, 2019). This review emphasizes the complexity of the cellular problem at hand with respect to interactions of iron with certain proteins and small molecules as caused by HF.…”

Section: Resultsmentioning

confidence: 99%

Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

2019

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Cellular growth, function, and protection require proper iron management, and ferritin plays a crucial role as the major iron sequestration and storage protein. Ferritin is a 24 subunit spherical shell protein composed of both light (FTL) and heavy chain (FTH1) subunits, possessing complimentary iron-handling functions and forming threefold and four-fold pores. Iron uptake through the threefold pores is well-defined, but the unloading process somewhat less and generally focuses on lysosomal ferritin degradation although it may have an additional, energetically efficient pore mechanism. Hereditary Ferritinopathy (HF) or neuroferritinopathy is an autosomal dominant neurodegenerative disease caused by mutations in the FTL C-terminal sequence, which in turn cause disorder and unraveling at the four-fold pores allowing iron leakage and enhanced formation of toxic, improperly coordinated iron (ICI). Histopathologically, HF is characterized by iron deposition and formation of ferritin inclusion bodies (IBs) as the cells overexpress ferritin in an attempt to address iron accumulation while lacking the ability to clear ferritin and its aggregates. Overexpression and IB formation tax cells materially and energetically, i.e., their synthesis and disposal systems, and may hinder cellular transport and other spatially dependent functions. ICI causes cellular damage to proteins and lipids through reactive oxygen species (ROS) formation because of high levels of brain oxygen, reductants and metabolism, taxing cellular repair. Iron can cause protein aggregation both indirectly by ROS-induced protein modification and destabilization, and directly as with mutant ferritin through C-terminal bridging. Iron release and ferritin degradation are also linked to cellular misfunction through ferritinophagy, which can release sufficient iron to initiate the unique programmed cell death process ferroptosis causing ROS formation and lipid peroxidation. But IB buildup suggests suppressed ferritinophagy, with elevated iron from four-fold pore leakage together with ROS damage and stress leading to a long-term ferroptotic-like state in HF. Several of these processes have parallels in cell line and mouse models. This review addresses the roles of ferritin structure and function within the above-mentioned framework, as they relate to HF and associated disorders characterized by abnormal iron accumulation, protein aggregation, oxidative damage, and the resulting contributions to cumulative cellular stress and death.

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Section: Resultsmentioning

confidence: 99%

Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

2019

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“…Ferroptosis is implicated in numerous human diseases and pathologies. It has been suggested that ferroptosis plays a role in the progression of degenerative diseases of the kidney, heart, liver, and brain (Feng and Stockwell, 2018); stroke, Alzheimer disease, Huntington disease (HD), and Parkinson disease are among the candidates for neurodegenerative diseases that may involve ferroptosis (Weiland et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Transferrin Receptor Is a Specific Ferroptosis Marker

et al. 2020

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“…Activation of the ferroptosis pathways has been connected with the growing number of disorders including AD and PD. [ 166 ] Inhibiting ferroptosis by small molecules or by gene knockdown can protect neurons, and improve the cognitive function in the diseased animal. For example, mitochondrial dysfunction and ferroptosis can be suppressed by targeting nuclear factor erythroid 2‐related factor (2NRF2) in neurodegenerative diseases.…”

Section: Safety Challenges Of Nanomedicinementioning

confidence: 99%

“…[ 170 ] For several other ferroptosis inhibitors please refer to the recent review article by Wang and co‐workers. [ 166 ]…”

Section: Safety Challenges Of Nanomedicinementioning

confidence: 99%

Recent Advancements of Nanomedicine in Neurodegenerative Disorders Theranostics

Mukherjee

Madamsetty

Bhattacharya

et al. 2020

Adv Funct Materials

100

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Recent times have witnessed an upsurge in the incidence of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Prion disease, and amyotrophic lateral sclerosis. The treatment of the same remains a daunting challenge due to the limited access of therapeutic moieties across the blood–brain barrier. Engineered nanoparticles with a size less than 100 nm provide multifunctional abilities for solving these biomedical and pharmacological issues due to their unique physico‐chemical properties along with capability to cross the blood–brain barrier. Needless to mention, there is a scarcity of review articles summarizing recent developments of various nanomaterials including liposomes, polymeric nanoparticles, metal nanoparticles, and bio‐nanoparticles toward the therapeutic and theranostics applications for various neurodegenerative disorders. Here, a broad spectrum of nanomedicinal approaches to eradicate neurodegenerative disorders is provided, along with a brief account of neuroprotection and neuronal tissue regeneration, current clinical status, issues related to safety, toxicity, challenges, and future outlook.

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Ferroptosis and Its Role in Diverse Brain Diseases

Cited by 362 publications

References 164 publications

Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

Transferrin Receptor Is a Specific Ferroptosis Marker

Recent Advancements of Nanomedicine in Neurodegenerative Disorders Theranostics

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