Structure, Function, Folding, and Aggregation of a Neuroferritinopathy-Related Ferritin Variant

Kuwata, Takumi; Okada, Yuta; Yamamoto, Tomoki; Sato, Daisuke; Fujiwara, Kazuo; Fukumura, Takuma; Ikeguchi, Masamichi

doi:10.1021/acs.biochem.8b01068

Cited by 14 publications

(3 citation statements)

References 32 publications

(76 reference statements)

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“…The second case consists of a missense mutation (A96T) in the FTL gene in an individual without significant involvement of the putamen, thalamus, and substantia nigra that did not show autosomal dominant transmission since the mother of the proband, also a carrier of the A96T mutation, had similar MRI findings and was asymptomatic (Maciel et al, 2005). The A96T variant has been recently shown to be stable under physiological conditions and incorporate iron comparable to that of wild-type FTL ferritin (Kuwata et al, 2019).…”

Section: Genetics Clinical Presentation and Pathology Of Hfmentioning

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: Genetics Clinical Presentation and Pathology Of Hfmentioning

confidence: 99%

Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

2019

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“…Such aggregates scatter X-rays strongly and interfere with the interpretation of SAXS data. Recombinant human ferritin H-chain and L-chain This article is part of a Special Issue dedicated to the '2018 Joint Conference of the Asian Biophysics Association and Australian Society for Biophysics' edited by Kuniaki Nagayama, Raymond Norton, Kyeong Kyu Kim, Hiroyuki Noji, Till Böcking, and Andrew Battle. were reported to show similar irreversible denaturation (Kuwata et al 2019;Santambrogio et al 1993). In contrast to mammalian ferritins, bacterial ferritins are composed of the same kind of subunits resembling H-chain of mammalian ferritins.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of ferritin assembly studied by time-resolved small-angle X-ray scattering

Sato

Ikeguchi

2019

Biophys Rev

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The assembly reaction of Escherichia coli ferritin A (EcFtnA) was studied using time-resolved small-angle X-ray scattering (SAXS). EcFtnA forms a cage-like structure that consists of 24 identical subunits and dissociates into dimers at acidic pH. The dimer maintains native-like secondary and tertiary structures and can reassemble into a 24-mer when the pH is increased. The time-dependent changes in the SAXS profiles of ferritin during its assembly were roughly explained by a simple model in which only tetramers, hexamers, and dodecamers were considered intermediates. The rate of assembly increased with increasing ionic strength and decreased with increasing pH (from pH 6 to pH 8). These tendencies might originate from repulsion between assembly units (dimers) with the same net charge sign. To test this hypothesis, ferritin mutants with different net charges (netcharge mutants) were prepared. In buffers with low ionic strength, the rate of assembly increased with decreasing net charge. Thus, repulsion between the assembly unit net charges was an important factor influencing the assembly rate. Although the differences in the assembly rate among net-charge mutants were not significant in buffers with an ionic strength higher than 0.1, the assembly rates increased with increasing ionic strength, suggesting that local electrostatic interactions are also responsible for the ionic-strength dependence of the assembly rate and are, on average, repulsive.

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“…These variants were shown to cause changes in amino acid sequence creating subunits that assemble into ferritin polymers with altered structure and/or much larger pores than the wild type. Polymers containing mutated protein presumably have lower stability and reduced Fe retention ability leading to an increased cytosolic labile Fe pool [159,162,163]. Neuroferritinopathy is manifested by low serum ferritin along with pathological Fe deposits localized in various brain regions, most consistently in the globus pallidus, SN, and dentate nucleus, but also in the putamen, caudate, and deeper cortical layers (Table 1) [164].…”

Section: Neurodegenerations With Brain Iron Accumulation (Nbia) Groupmentioning

confidence: 99%

Cerebral Iron Deposition in Neurodegeneration

et al. 2022

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Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

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Structure, Function, Folding, and Aggregation of a Neuroferritinopathy-Related Ferritin Variant

Cited by 14 publications

References 32 publications

Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

Mechanisms of ferritin assembly studied by time-resolved small-angle X-ray scattering

Cerebral Iron Deposition in Neurodegeneration

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