Abstract
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.
Highlights
Beta-propeller protein-associated neurodegeneration (BPAN) caused by mutations in the autophagy gene WD Repeat Domain 45 (WDR45), which encodes WD-repeat protein interacting with phosphoinositides 4 (WIPI4) has emerged as the most common Neurodegeneration with brain iron accumulation (NBIA) disorder [2,3]
Iron Accumulation Was Confirmed in WDR45 Mutant Fibroblasts
We examined iron accumulation and localization in WDR45 mutant fibroblasts
Summary
Beta-propeller protein-associated neurodegeneration (BPAN) caused by mutations in the autophagy gene WD Repeat Domain 45 (WDR45), which encodes WD-repeat protein interacting with phosphoinositides 4 (WIPI4) has emerged as the most common NBIA disorder [2,3]. It is characterized by childhood developmental delay and seizures, followed by parkinsonism and dystonia, as well as dementia, in adolescence or early adulthood [2,3,4]. We investigated iron accumulation in WDR45 mutant fibroblast cells from a patient and studied the relationship between iron accumulation, defects in autophagy and mitochondrial dysfunction through structural and functional analysis. To investigate the structural and functional changes in autophagy and mitochondria caused by iron accumulation, such changes were measured using confocal microscopy, electron microscopy, and gene expression profiling analysis
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