Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells
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- Philip Seibler
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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- Lena F Burbulla
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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- Marija Dulovic
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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- Simone Zittel
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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- Johanne Heine
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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- Thomas Schmidt
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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- Franziska Rudolph
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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- Ana Westenberger
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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- Aleksandar Rakovic
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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- Alexander Münchau
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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- Dimitri Krainc
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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- Christine Klein
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
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説明
<jats:title>Abstract</jats:title> <jats:p>Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.</jats:p>
収録刊行物
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- Brain
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Brain 141 (10), 3052-3064, 2018-08-30
Oxford University Press (OUP)