Journal
BRAIN
Volume 141, Issue -, Pages 3052-3064Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awy230
Keywords
WDR45; iron; autophagy; mitochondria; dopaminergic neurons
Categories
Funding
- Hermann and Lilly Schilling Foundation
- Federal Ministry of Education and Research (DysTract)
- German Research Foundation [FOR2488]
- [R01 NS076054]
- [R01 NS096240]
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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 diseasecausing 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.
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