Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells

Philip Seibler, Lena F. Burbulla, Marija Dulovic, Simone Zittel, Johanne Heine, Thomas Schmidt, Franziska Rudolph, Ana Westenberger, Aleksandar Rakovic, Alexander Münchau, Dimitri Krainc, Christine Klein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3052-3064
Number of pages13
JournalBrain
Volume141
Issue number10
DOIs
StatePublished - Oct 1 2018

Keywords

  • WDR45
  • autophagy
  • dopaminergic neurons
  • iron
  • mitochondria

ASJC Scopus subject areas

  • Clinical Neurology

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