WDR45 Mutation Impairs the Autophagic Degradation of Transferrin Receptor and Promotes Ferroptosis

Xiong, Qiuhong; Li, Xin; Li, Wenjing; Chen, Guangxin; Han, Xiao; Li, Ping; Wu, Changxin

doi:10.3389/fmolb.2021.645831

Cited by 43 publications

(27 citation statements)

References 51 publications

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“…This phenotype suggests that the inability of cells to obtain the iron stored in ferritin generates a deregulated iron uptake, possibly as a compensatory response. Another mechanism that could contribute to iron accumulation is the deficiency in the autophagic degradation of TfR1, also observed in WDR45-mutant cells [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

New Players in Neuronal Iron Homeostasis: Insights from CRISPRi Studies

et al. 2022

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Selective regional iron accumulation is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. The underlying mechanisms of neuronal iron dyshomeostasis have been studied, mainly in a gene-by-gene approach. However, recent high-content phenotypic screens using CRISPR/Cas9-based gene perturbations allow for the identification of new pathways that contribute to iron accumulation in neuronal cells. Herein, we perform a bioinformatic analysis of a CRISPR-based screening of lysosomal iron accumulation and the functional genomics of human neurons derived from induced pluripotent stem cells (iPSCs). Consistent with previous studies, we identified mitochondrial electron transport chain dysfunction as one of the main mechanisms triggering iron accumulation, although we substantially expanded the gene set causing this phenomenon, encompassing mitochondrial complexes I to IV, several associated assembly factors, and coenzyme Q biosynthetic enzymes. Similarly, the loss of numerous genes participating through the complete macroautophagic process elicit iron accumulation. As a novelty, we found that the impaired synthesis of glycophosphatidylinositol (GPI) and GPI-anchored protein trafficking also trigger iron accumulation in a cell-autonomous manner. Finally, the loss of critical components of the iron transporters trafficking machinery, including MON2 and PD-associated gene VPS35, also contribute to increased neuronal levels. Our analysis suggests that neuronal iron accumulation can arise from the dysfunction of an expanded, previously uncharacterized array of molecular pathways.

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Section: Resultsmentioning

confidence: 99%

New Players in Neuronal Iron Homeostasis: Insights from CRISPRi Studies

et al. 2022

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“…Xiong et al reported that WDR45-deficient cells showed transferrin receptor accumulation, which affects autophagic degradation. They also suggested that WDR45 mutation could promote ferroptosis by lipid peroxidation and ROS production [ 16 ]. ROS from iron metabolism can induce ferroptosis; it is also correlated with NADPH oxidase activity and lipid peroxidation products.…”

Section: Discussionmentioning

confidence: 99%

Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts

Lee

Jung

Noh

et al. 2021

IJMS

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Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G>A in WD Repeat Domain 45 (WDR45), showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on cellular organelles, including lipid droplets, mitochondria and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria and increased numbers of lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload.

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“…Impaired ferritinophagy and non-transferrin-bound iron pathway were confirmed to mediate the accumulation of iron in another cellular BPAN model [234] whereby iron was detected mostly in lysosomal vesicles [235]. Yet another study employing the cellular BPAN model found accumulation of TfR in cells overexpressing mutated WDR45 that was associated with increased Fe levels [236]. Interestingly, increased ratio between serum concentration of soluble TfR and logarithm of serum ferritin concentration (sTfR/logFerrit) was observed in five BPAN patients, suggesting complex systemic disruption of Fe metabolism [86].…”

Section: Neurodegenerations With Brain Iron Accumulation (Nbia) Groupmentioning

confidence: 90%

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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WDR45 Mutation Impairs the Autophagic Degradation of Transferrin Receptor and Promotes Ferroptosis

Cited by 43 publications

References 51 publications

New Players in Neuronal Iron Homeostasis: Insights from CRISPRi Studies

New Players in Neuronal Iron Homeostasis: Insights from CRISPRi Studies

Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts

Cerebral Iron Deposition in Neurodegeneration

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