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

Brain : a Journal of Neurology
Philip SeiblerChristine Klein

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.

References

Jul 31, 1996·Biochimica Et Biophysica Acta·P M Harrison, P Arosio
Jul 4, 2006·Movement Disorders : Official Journal of the Movement Disorder Society·Daniela Berg, Helmine Hochstrasser
Jul 29, 2006·The EMBO Journal·Mark J BarsoumElla Bossy-Wetzel
Feb 9, 2008·Histochemistry and Cell Biology·Tino KurzUlf T Brunk
Jul 5, 2008·Nature Protocols·In-Hyun ParkGeorge Q Daley
Feb 10, 2009·Methods in Enzymology·Susmita Kaushik, Ana Maria Cuervo
Oct 8, 2009·Human Molecular Genetics·Hsiuchen Chen, David C Chan
Mar 2, 2010·FEBS Letters·Isabelle Vergne, Vojo Deretic
Apr 22, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Philip SeiblerDimitri Krainc
Nov 28, 2012·American Journal of Human Genetics·Tobias B HaackSusan J Hayflick
May 21, 2013·Brain : a Journal of Neurology·Susan J HayflickPenelope Hogarth
Jul 4, 2013·Nature Reviews. Neuroscience·Tracey A Rouault
Aug 7, 2013·Journal of Molecular Cell Biology·Hanna AppelqvistKarin Öllinger
May 3, 2014·Neurology. Clinical Practice·Yuta IchinoseYoshihisa Takiyama
Sep 19, 2014·Lancet Neurology·Roberta J WardLuigi Zecca
Jan 9, 2015·Journal of Cell Science·Tassula Proikas-CezanneOliver Kohlbacher
Feb 4, 2016·Proceedings of the National Academy of Sciences of the United States of America·Joseph R MazzulliDimitri Krainc

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Citations

Mar 12, 2019·Journal of Inherited Metabolic Disease·Julian TeinertDarius Ebrahimi-Fakhari
Apr 11, 2019·Brain : a Journal of Neurology·Musharraf JelaniJamal Nasir
Jun 10, 2020·Brain : a Journal of Neurology·Ana CascalhoRose E Goodchild
Apr 2, 2019·Frontiers in Neuroscience·Maria Quiles Del Rey, Joseph D Mancias
Jun 12, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Wesley PengDimitri Krainc
May 7, 2020·Frontiers in Cell and Developmental Biology·Daniela Bakula, Morten Scheibye-Knudsen
Apr 2, 2020·Frontiers in Cellular Neuroscience·Anna FassioFabio Benfenati
Nov 21, 2020·Molecular Neurodegeneration·Jerome RobertCheryl L Wellington
Apr 13, 2021·Autophagy·Yingying CongMario Mauthe
Nov 14, 2020·Journal of Neural Transmission·Rebecca HerzogAlexander Münchau
May 21, 2021·Frontiers in Molecular Biosciences·Qiuhong XiongChangxin Wu
May 28, 2021·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Caroline A BiagoschArcangela Iuso
Jul 30, 2021·American Journal of Medical Genetics. Part a·Jae-Hyeok LeeJi Young Mun
Apr 20, 2021·Brain : a Journal of Neurology·Edoardo MonfriniAlessio Di Fonzo
Nov 28, 2021·Journal of Neurochemistry·Luisa AringYoung Ah Seo
Dec 16, 2021·Tremor and Other Hyperkinetic Movements·Robert V V SpaullManju A Kurian

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