The Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System

Joppe, Karina; Roser, Anna-Elisa; Maass, Fabian; Lingor, Paul

doi:10.3389/fnins.2019.00015

Cited by 74 publications

(72 citation statements)

References 135 publications

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“…Moreover, it indicates new strategies to develop brain-targeted metal chelators. Iron chelators have been deemed therapeutically useful in PD and other neurodegenerative conditions (Dunaief 2011;Joppe et al 2019;Kaindlstorfer et al 2018;Ndayisaba et al 2019). However, their exact effects on brain pathophysiology have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Design and evaluation of bi-functional iron chelators for protection of dopaminergic neurons from toxicants

et al. 2020

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While the etiology of non-familial Parkinson's disease (PD) remains unclear, there is evidence that increased levels of tissue iron may be a contributing factor. Moreover, exposure to some environmental toxicants is considered an additional risk factor. Therefore, brain-targeted iron chelators are of interest as antidotes for poisoning with dopaminergic toxicants, and as potential treatment of PD. We, therefore, designed a series of small molecules with high affinity for ferric iron and containing structural elements to allow their transport to the brain via the neutral amino acid transporter, LAT1 (SLC7A5). Five candidate molecules were synthesized and initially characterized for protection from ferroptosis in human neurons. The promising hydroxypyridinone SK4 was characterized further. Selective iron chelation within the physiological range of pH values and uptake by LAT1 were confirmed. Concentrations of 10-20 µM blocked neurite loss and cell demise triggered by the parkinsonian neurotoxicants, methyl-phenyl-pyridinium (MPP +) and 6-hydroxydopamine (6-OHDA) in human dopaminergic neuronal cultures (LUHMES cells). Rescue was also observed when chelators were given after the toxicant. SK4 derivatives that either lacked LAT1 affinity or had reduced iron chelation potency showed altered activity in our assay panel, as expected. Thus, an iron chelator was developed that revealed neuroprotective properties, as assessed in several models. The data strongly support the role of iron in dopaminergic neurotoxicity and suggests further exploration of the proposed design strategy for improving brain iron chelation.

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Section: Discussionmentioning

confidence: 99%

Design and evaluation of bi-functional iron chelators for protection of dopaminergic neurons from toxicants

et al. 2020

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“…Under physiological conditions, tau is a microtubuleassociated protein that supports neuronal microtubule structure, which plays a key role in axonal transport, protein trafficking, and cognitive function (Wang and Mandelkow, 2016;Joppe et al, 2019). However, tau hyperphosphorylation aggregates into NFTs, which is a major pathological hallmark of AD.…”

Section: Iron Metabolism Linking With Ad Pathologymentioning

confidence: 99%

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

2020

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Iron is an essential transition metal for numerous biologic processes in mammals. Iron metabolism is regulated via several coordination mechanisms including absorption, utilization, recycling, and storage. Iron dyshomeostasis can result in intracellular iron retention, thereby damaging cells, tissues, and organs through free oxygen radical generation. Numerous studies have shown that brain iron overload is involved in the pathological mechanism of neurodegenerative disease including Alzheimer's disease (AD). However, the underlying mechanisms have not been fully elucidated. Ferroptosis, a newly defined iron-dependent form of cell death, which is distinct from apoptosis, necrosis, autophagy, and other forms of cell death, may provide us a new viewpoint. Here, we set out to summarize the current knowledge of iron metabolism and ferroptosis, and review the contributions of iron and ferroptosis to AD.

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“…112 Iron is often a component of these disease-associated protein aggregates and in the case of some such proteins directly induces their misfolding, fibrillization, and aggregation. 113 Another common denominator of age-associated neurodegenerative diseases is oxidative stress. The brain is particularly vulnerable to mitochondrial dysfunction and the generation of toxic free-radicals.…”

Section: Age-associated Neurodegenerative Diseasesmentioning

confidence: 99%

Overdosing on iron: Elevated iron and degenerative brain disorders

D’Mello¹,

Kindy

2020

Exp Biol Med (Maywood)

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All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

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The Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System

Cited by 74 publications

References 135 publications

Design and evaluation of bi-functional iron chelators for protection of dopaminergic neurons from toxicants

Design and evaluation of bi-functional iron chelators for protection of dopaminergic neurons from toxicants

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

Overdosing on iron: Elevated iron and degenerative brain disorders

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