A neurodegeneration gene, <i>WDR45</i>, links impaired ferritinophagy to iron accumulation

Aring, Luisa; Choi, Eun‐Kyung; Kopera, Huira C.; Lanigan, Thomas M.; Iwase, Shigeki; Klionsky, Daniel J.; Seo, Young Ah

doi:10.1111/jnc.15548

Cited by 23 publications

(15 citation statements)

References 101 publications

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“…Patient-derived fibroblasts present lysosomal Fe 2+ accumulation, lysosomal enlargement, and a fragmented mitochondrial network [ 47 ]. WDR45-deficient neuroblastoma cells show impaired ferritinophagy, increased non-Tf bound iron uptake, elevated mitochondrial iron levels, and deficits in mitochondrial respiration [ 48 ]. 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.…”

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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“…As a subtype of neurodegeneration with brain iron accumulation (NBIA), iron accumulates in the globus pallidus and substantia nigra [ 3 ]. Several studies have shown that ferritin dysregulation in WDR45 deficient cells consequently disrupts iron homeostasis [ 36 , 43 – 46 ]. Iron accumulation may lead to ferroptosis, which promotes BPAN; however, treatment with iron chelation drugs has no benefit and can even worsen this process [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

Lipid droplet accumulation in Wdr45-deficient cells caused by impairment of chaperone-mediated autophagic degradation of Fasn

Xiong,

Sun,

Wang

et al. 2024

Lipids Health Dis

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Background β-Propeller protein-associated neurodegeneration (BPAN) is a genetic neurodegenerative disease caused by mutations in WDR45. The impairment of autophagy caused by WDR45 deficiency contributes to the pathogenesis of BPAN; however, the pathomechanism of this disease is largely unknown. Lipid dyshomeostasis is involved in neurogenerative diseases, but whether lipid metabolism is affected by Wdr45 deficiency and whether lipid dyshomeostasis contributes to the progression of BPAN are unclear. Methods We generated Wdr45 knockout SN4741 cell lines using CRISPR‒Cas9-mediated genome editing, then lipid droplets (LDs) were stained using BODIPY 493/503. Chaperone-mediated autophagy was determined by RT-qPCR and western blotting. The expression of fatty acid synthase (Fasn) was detected by western blot in the presence or absence of the lysosomal inhibitor NH4Cl and the CMA activator AR7. The interaction between Fasn and HSC70 was analyzed using coimmunoprecipitation (Co-IP) assay. Cell viability was measured by a CCK-8 kit after treatment with the Fasn inhibitor C75 or the CMA activator AR7. Results Deletion of Wdr45 impaired chaperone-mediated autophagy (CMA), thus leading to lipid droplet (LD) accumulation. Moreover, Fasn can be degraded via CMA, and that defective CMA leads to elevated Fasn, which promotes LD formation. LD accumulation is toxic to cells; however, cell viability was not rescued by Fasn inhibition or CMA activation. Inhibition of Fasn with a low concentration of C75 did not affect cell viability but decreases LD density. Conclusions These results suggested that Fasn is essential for cell survival but that excessive Fasn leads to LD accumulation in Wdr45 knockout cells.

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“…This pattern of molecular abnormalities led to the hypothesis that mutations in WDR45 may affect ferritinophagy and mitophagy causing deranged Fe recycling with DMT1 upregulation as a proximal cause of Fe accumulation [224]. 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].…”

Section: Neurodegenerations With Brain Iron Accumulation (Nbia) Groupmentioning

confidence: 96%

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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A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 23 publications

References 101 publications

New Players in Neuronal Iron Homeostasis: Insights from CRISPRi Studies

New Players in Neuronal Iron Homeostasis: Insights from CRISPRi Studies

Lipid droplet accumulation in Wdr45-deficient cells caused by impairment of chaperone-mediated autophagic degradation of Fasn

Cerebral Iron Deposition in Neurodegeneration

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