WDR45 variants cause ferrous iron loss due to impaired ferritinophagy associated with nuclear receptor coactivator 4 and WD repeat domain phosphoinositide interacting protein 4 reduction. Issue 6 (23rd November 2022)

• Record Type: Journal Article
• Authors: Tsukida, Kiwako; Muramatsu, Shin-ichi; Osaka, Hitoshi; Yamagata, Takanori; Muramatsu, Kazuhiro
• Is Part Of: Brain communications. Volume 4:Issue 6(2022)
• Publication Date: 2022-11-23
• Subjects: SENDA/BPAN -- WDR45/WIPI4 -- iron metabolism -- NCOA4 -- ferittinophagy; 616
• DOI: 10.1093/braincomms/fcac304
• Languages: English
• ISSNs: 2632-1297

Abstract

Abstract: Static encephalopathy of childhood with neurodegeneration in adulthood/β-propeller protein-associated neurodegeneration is a neurodegenerative disorder with brain iron accumulation caused by the variants of WDR45, a core autophagy-related gene that encodes WD repeat domain phosphoinositide interacting protein 4. However, the pathophysiology of the disease, particularly the function of WDR45 /WD repeat domain phosphoinositide interacting protein 4 in iron metabolism, is largely unknown. As no other variants of core autophagy-related genes show abnormalities in iron metabolism, the relation between autophagy and iron metabolism remains to be elucidated. Since iron deposition in the brain is the hallmark of static encephalopathy of childhood with neurodegeneration in adulthood/β-propeller protein-associated neurodegeneration, iron chelation therapy has been attempted, but it was found to worsen the symptoms; thus, the establishment of a curative treatment is essential. Here, we evaluated autophagy and iron metabolism in patient-derived cells. The expression of ferritin and ferric iron increased and that of ferrous iron decreased in the patient cells with WDR45 variants. In addition, the expression of nuclear receptor coactivator 4 was markedly reduced in patient-derived cells. Furthermore, divalent metal transporter 1, which takes in ferrous iron, was upregulated, while ferroportin, which exports ferrous iron, was downregulated in patient-derived cells. The transfer of WDR45 via an adeno-associated virus vector restored WD repeat domain phosphoinositide interacting protein 4 and nuclear receptor coactivator 4 expression, reduced ferritin levels, and improved other phenotypes observed in patient-derived cells. As nuclear receptor coactivator 4 mediates the ferritin-specific autophagy, i.e. ferritinophagy, its deficiency impaired ferritinophagy, leading to the accumulation of ferric iron-containing ferritin and insufficiency of ferrous iron. Because ferrous iron is required for various essential biochemical reactions, the changes in divalent metal transporter 1 and ferroportin levels may indicate a compensatory response for maintaining the intracellular levels of ferrous iron. Our study revealed that the pathophysiology of static encephalopathy of childhood with neurodegeneration in adulthood/β-propeller protein-associated neurodegeneration involves ferrous iron insufficiency via impaired ferritinophagy through nuclear receptor coactivator 4 expression reduction. Our findings could aid in developing a treatment strategy involving WDR45 manipulation, which may have clinical applications. Abstract : Tsukida et al . found WD repeat domain 45 variants cause deficiency of nuclear receptor coactivator 4, which mediates ferritinophagy in the autophagy-related neurodegenerative disease, static encephalopathy of childhood with neurodegeneration in adulthood/β-propeller protein-associated neurodegeneration. Impaired ferritinophagy results in ferric iron accumulation within ferritin and damages cellular function by ferrous iron deficiency. Gene transfer rescues these phenotypes. Graphical Abstract: Graphical abstract Video Abstract: